Ignite Creation Date:
2024-05-05 @ 12:10 PM
Last Modification Date:
2024-10-26 @ 9:21 AM
Study NCT ID:
NCT00268814
Status:
COMPLETED
Last Update Posted:
2015-09-09
First Post:
2005-12-21
Brief Title:
The German Project of Heroin Assisted Treatment of Opiate Dependent Patients
Sponsor:
Universitätsklinikum Hamburg-Eppendorf
Organization:
Universitätsklinikum Hamburg-Eppendorf
Study Overview
Official Title:
Phase III Study of Maintenance Treatment for Opiate Dependence With Heroin Diamorphine Compared to Methadone
Status:
COMPLETED
Status Verified Date:
2015-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The study will test the hypotheses that heroin assisted treatment compared to methadone maintenance treatment is more effective with regard to
the improvement of health
reduction of illicit drug consumption
decrease of criminal behaviour
rise in the accessibility and retainment
detachment from a social drug context
social stabilisation in the sense of new drug-free contacts improved vocational circumstances financial security stabilisation of the living situation
enrollment in subsequent treatment in the case of heroin dependent persons who could not be effectively reached or successfully treated so far and it will check which is the optimal treatment setting with regard to these aims
The medication is injectable pure heroin diacetylmorphine 3xd or d l methadone 1xd
The study design is multicentre open randomised 4 x 2 stratified The study duration is 24 months individual period of investigation 1 study phase 12 moths protocol part B and 2 study phase 12 moths part C Patients recruited have an opiate dependency according to ICD-10 who are not being treated currently or who are in a methadone maintenance programme with an unsatisfactory course of treatment
the improvement of health
reduction of illicit drug consumption
decrease of criminal behaviour
rise in the accessibility and retainment
detachment from a social drug context
social stabilisation in the sense of new drug-free contacts improved vocational circumstances financial security stabilisation of the living situation
enrollment in subsequent treatment in the case of heroin dependent persons who could not be effectively reached or successfully treated so far and it will check which is the optimal treatment setting with regard to these aims
The medication is injectable pure heroin diacetylmorphine 3xd or d l methadone 1xd
The study design is multicentre open randomised 4 x 2 stratified The study duration is 24 months individual period of investigation 1 study phase 12 moths protocol part B and 2 study phase 12 moths part C Patients recruited have an opiate dependency according to ICD-10 who are not being treated currently or who are in a methadone maintenance programme with an unsatisfactory course of treatment
Detailed Description:
Detailed description of study phase 1 randomized controlled part of study only
Part B - Study phase 1 B11 Clinical hypothesis Compared to maintenance with oral methadone heroin treatment leads to
significant improvement of the physical andor mental state of health
greater reduction of illicit drug use and therefore greater detachment from the drug scene
significant improvement of the social situation
higher retention rate or attachment to treatment in the case of those heroin dependent persons who could not be effectively reached or could not sufficiently profit from methadone maintenance programmes
B12 Primary outcome criteria
Improvement of the physical and mental state of health A AND
Reduction of illicit heroin use and non-increase of cocaine use B B13 Secondary outcome criteria
Retention rate
Reduction of benzodiazepine amphetamine alcohol and other drug use
Reduction of scene contacts of contacts to other drug consumers
Decrease of delinquent behaviour
Stabilisation of housing situation
Establishment of new social contacts
Improvement of quality of life
Mortality rate B2 STUDY DESIGN Phase 1 of the clinical trial consists in a 4 x 2-branched randomised multicentre study The sample is stratified and consists on the one hand of heroin dependent persons in methadone maintenance treatment that do not sufficiently profit from treatment MS and on the other hand of heroin dependent persons who are currently not being treated for their addiction NE Patients of both target groups who meet the admission criteria will be randomised to four arms experimental groups MS-E-C and NE-E-C heroin treatment with concurrent case management experimental groups MS-E-P and NE-E-P heroin treatment with concurrent psychoeducationdrug counseling and control groups MS-K-C and NE-K-C methadone treatment with concurrent case management control groups MS-K-P and NE-K-P methadone treatment with concurrent psychoeducationdrug counseling
B22 Recruitment of patients The period of registration is not part of the individual study period A screening is carried out at registration concerning certain inclusion criteria The patients are given the opportunity of a thorough information concerning the conditions and course of the study
First of all patients are asked to sign their consent to participate in the study This is followed by the indication assessment T-1 by the study physician and the external interview EuropASI Certain particularly medical characteristics are again examined at the beginning of treatment T0
The regionally responsible study physician will decide on the inclusion in the study His decision needs the confirmation of a regional committee of experts
B23 Randomisation The allocation to treatment places of the experimental or control group is carried out according to a randomisation code Randomisation is done separately for both groups MS and NE based on permuted blocks of fixed size
After the evaluation of the indication assessment and the first interview at T-1 patients who have been recruited and who fulfil the inclusion criteria are then asked to give a second consent of participation in the study and the results of randomisation will be communicated to them
B24 Course of the study examinations and times of the investigations The first phase of the clinical trial covers a period of 12 months All questioning is done in a personal interview face to face with the assurance that all information will be confidential
All patients who take part in the interviews receive an expense allowance of Euro 15- for each survey
A hair sample is already taken at the indication examination T-1 This allows taking a hair sample fit for analysis at the beginning of treatment T0 from those patients whose hair was too short at T-1 The CIDI will be carried out after one month of treatment in order to minimise initial influences requiring treatment
In order to determine the use of illicit heroin which is a main target criterion five urine controls will be thoroughly examined by GCMS both in the 6th and the 12th month of treatment
B3 PATIENTS The adequate treatment of the questions posed by this study requires a number of at least 140 patients in each test group 4 experimental and 4 control groups Therefore the sample size for the entire study will be N1120
B31 Inclusion criteria
Patients who fulfil following criteria can be included in the study
Minimum age 23 years
Opiate dependence for at least 5 years
Current main diagnosis of opiate dependency according to the ICD-10 criteria
Current daily and predominantly intravenous heroin use or continuing heroin use in maintenance treatment
Symptoms of physical illness indicating a poor state of health according to the OTI health scale at least 13 current symptoms must be found OR Current mental symptoms or disturbances ie a standardised GSI value of the SCL-90-R of at least 60 points
No participation in an addiction treatment programme aa maintenance inpatient or outpatient treatment at least within the last 6 months but documented previous experience with drug therapies OR Negative course of maintenance treatment according to the guidelines of the German Medical Council due to a continuous additional use of heroin 50 of the urine samples positive within the last 6 months or cocaine harmful use of cocainecrack according to ICD-10 in a documented maintenance period of at least 6 months with a current maintenance dose of at least 60 mg d l methadone or 30 mg levomethadone daily
Residence in the city or city state or region for at least 12 months
Voluntary participation and ability to comply with the treatment conditions
Written consent to comply with the treatment conditions B32 Exclusion criteria
Persons with at least one of the following criteria cannot be included in the study
Persons who are currently in prison or awaiting trial or who can be expected to be taken into custody within the next 3 months
Persons who had voluntary phases of abstinence of at least 2 months during the last 12 months
Known epilepsy or generalised convulsions during the last 12 months
Hypersensitivity to test substances and additives
Regular intake of MAO inhibitors
Serious bronchial asthma COPD Cor pulmonale
Serious cardiac arrhythmia
Prostatic hypertrophy with urinary retention
Urethral stricture
Life threatening liver disorders exogenous hepatic coma
Serious renal disorders
Insulin dependent diabetes mellitus
Diagnosed malignancies during the last 6 months
Pregnant women or nursing mothers
Patients unable to comply with the study conditions ie participation in the therapeutic and scientific programmes due to serious physical or mental illness
Patients who are currently participating in another clinical study concerned with the evaluation of an addiction treatment programme
B33 Dropping out of treatment
Participation in the study is voluntary ie the patient can withdraw his consent to be treated and to further participation in the study at any time Patients having at least one of the following characteristics are removed from treatment
Patients suffering from serious somatic complications in connection with heroin or methadone treatment for whom a continuation of treatment would be irresponsible in the opinion of the test study physician and the safety board
Patients with abnormally changed laboratory values for whom a continuation of treatment would incur great health risks according to the safety boards decision
Patients who have not turned up at the treatment centre or who have discontinued the study medication for a period of 14 days or longer for self-provoked reasons or without giving reasons
Patients who are taken into custody for one month or longer
Heroin patients whose treatment must be discontinued for more than 3 months due to hospitalisation or other special treatments
Patients who in the opinion of the study physician cannot or do not want to comply with the conditions of the model project any longer ie participation in the therapeutic and scientific programme
In case of violence threat of violence against persons involved in the project or other patients
In case of drug trafficking on the premises of the model project
In case of theft passing on or sale of prescribed substances B4 TREATMENT B41 Treatment setting Patients will be treated in an outpatient clinic The setting is based on at least weekly contacts to the treating physician Detailed physical examinations and blood counts 10 ml for each withdrawal take place at the start of treatment and after 1 3 6 and 12 months There will be weekly urine analyses qualitative proofs In addition a hair sample will be taken from an inconspicuous place at the back of the head at the beginning of treatment at admission after 6 months and at the examination after 12 months Patients under the influence of alcohol barbiturates or benzodiazepines can be refused their heroin or methadone dose If excessive alcohol consumption is suspected smell of alcohol a breath test is undertaken If the breath test is above 01 heroin or methadone will be refused
B43 Dose regimen Heroin in combination with methadone An additional medication of d-1 methadone at night will be offered from the start ie on the second day of treatment at the earliest The administration of heroin will occur up to 3 times a day during the opening hours of the setting in the morning at noon and in the evening In accordance with the Swiss and Dutch studies the maximum daily dose of iv heroin will be 1000 mg the single dose 400 mg If methadone is claimed at night it can be taken on the premises during the evening opening hours or taken out as a drinkable not injectable single dose The daily maximum dose of additionally prescribed dl methadone should not exceed 60 mg Methadone consumption will be controlled by regular urine analyses
Heroin will be handed out as injectable single doses in filled syringes and administered by the patient himself under observation Patients should stay in the centre for at least 30 minutes after the injection in order to control for possible unwanted effects
The different dose regimens dose regulation at the beginning of treatment or after interruptions starting from different points fading out in case of un-planned treatment conclusions are based on methadone daily equivalence doses MTQ According to the basic rule of the different dose regimens an individual dose of iv heroin for one day alone or in combination with oral methadone must not exceed the MTQ of the previous day by more than 50
Methadone Oral methadone will be administered once a day It is taken on the premises under observation as drinkable not injectable single dose There is no fixed maximum daily dose according to experience dosages between 40 and 160 mgd of methadone in individual cases up to 250 mgd must be expected A 1 methadone HCL solution is recommended
Dose regimen at the conclusion of treatment The conclusion of treatment is done by a step-by-step discontinuation of iv heroin or change to oral methadone The discontinuation of medication iv heroin alone or in combination with methadone will be done slowly Preferably the reduction should not be more than 10-20 of the MTQ of the previous day In most cases discontinuation can be completed within 2 weeks Possible withdrawal symptoms can be treated by concomitant medication
B5 VARIABLES B51 General patient characteristics General and specific sample characteristics such as gender age length of opiate dependency number of previous treatments current social situation are documented
B52 Medical examination and prescription data laboratory parameters The daily amounts of heroin or methadone handed out are registered and all further prescriptions are documented Medical examinations are documented in the CRF
B53 Pharmacokinetics Since pharmacokinetics the analgetic effects the tolerance effects and the addiction potential of heroin are well known and new findings are not to be expected within the framework of this study the study focuses mainly on questions concerning the effects and safety of medication
B54 Efficacy Primary outcome variables Efficacy is investigated with regard to two primary outcome measures - improvement of the state of health A and reduction of illicit drug consumption B These criteria will be evaluated independently by the statistical comparative analysis the success of one treatment in comparison to the other treatment is only proven if both analyses have significant results pointing in the same direction
State of health A
A1 Physical state of health
Number of symptoms according to the health scale of the Opiate Treatment Index OTI at T 1 and T12
VA1n OTI-Health Scale 0 VA1n 50
A2 Mental state of health
Global Severity Index GSI of the SCL-90-R at T 1 and T12 VA2n GSI value 0 VA2n 4
The treatment response concerning the improvement of the state of health is given if one of the two criteria VA1 or VA2 shows an improvement and the other criteria shows no aggravation Improvement and aggravation are defined as follows
For the physical state of health VA1 An improvement is indicated by a decrease on the OTI health scale by at least 20 and at least 4 points if T12 is compared with T-1 an aggravation is an increase of at least 20
For the mental state of health VA2 An improvement is indicated by a decrease of the GSI value by at least 20 if T12 is compared with T-1 an aggravation is an increase of at least 20
Illicit drug consumption B
B1 Use of illicit heroin
Number of illicit heroin-positive urine analyses during the 12 months of treatment ie among the last 5 urine samples before T12
VB1n number of positive urine samples 0 VB1 5 If the patient has dropped out of treatment and results at T12 are missing and the LOCF procedure is not possible because of missing urine samples in the 6th month of treatment but if at least one follow-up has occurred within the ITT method the patients self-reported data on use of illicit heroin physician-CRF will be used If these are also missing self-reported data from the external interview can be used This will be based on the number of days with illicit heroin consumption during the last 30 days VB1 before the corresponding time of investigation
VB1n number of illicit heroin consumption days 0 VB1 30
B2 Cocaine use
Cocaine concentration of hair based on hair analyses HAs at T-1 and T12 within following proof limits
VB2 n cocaine concentration VB2 n 1 μgg If the patient has dropped out of treatment if results at T12 are missing and the LOCF procedure is not possible because of missing HA at T6 but if at least one follow-up has occurred within the ITT method the patients self-reported data on cocaine consumption physician-CRF will be used If these are also missing self-reported data from the external interview can be used This will be based on the number of days with cocaine use during the last 30 days VB2 before the corresponding time of investigation
VB2n number of cocaine consumption days 0 VB2 30 HA does not represent the frequency but the integral intensity within the past period of observation assuming an average hair growth of 10 mm per month The lower limit of proof is assumed to be 1μgg An increase of cocaine consumption can be accurately proven if the value at T12 has increased by 30 in comparison to T-1 If the hair is too short - less than 15 cm - to take a sample at T-1 it will be done at T0
Decrease and non-increase of consumption are defined as follows
A decrease of illicit heroin use is assumed to be proven if not more than 2 of the 5 urine samples tested by GCMS by the 12th month of treatment are positive If only 4 urine samples are available by the 12th month of treatment only one urine sample may be positive to illicit heroin If only 3 urine samples are available none may be positive to illicit heroin in order to be rated as response If fewer urine samples are available by the 12th month of treatment the analyses at the 6th month will be used LOCF proceeding according to the same evaluation pattern Only if no usable urine analyses of the 6th month of treatment exist the patients self-report will be used VB1 A reduction of illicit heroin consumption of at least 60 between T-1 and T12 in relation to the number of consumption days during the last 30 days is rated as a response
The non-increase of cocaine use is proven by the provable cocaine concentration in the hair If a HA cannot be carried out at T12 the hair sample at T6 will be used LOCF Only if a usable HA is neither available at T6 due to a premature discontinuation of treatment the patients self report VB2 will be used A decrease or no change with a tolerance of 2 days of the number of consumption days within the last 30 days between T-1 and T12 is rated as a response Ie an increase of the number of days with cocaine consumption during the last month of not more than 2 days compared to T-1 is still rated as a response only an increase at T12 by more than 2 days is rated as non-response
It has to be assumed that a certain number of patients will prematurely before initiation of treatment or within the first 3 months drop-out of treatment in the case of methadone about 20 up to 40 in the case of heroin 10-20 but that they can be reached again for the examinations and investigations These patients can be summoned for examination at the fixed times but 5 urine samples during the last month will not be available from them These patients without valid data are rated as non-responders in the heroin group and as worst case responders in the methadone group Thus because a rather high percentage of dropouts in the control group have to be expected it would be hardly possible to prove the superiority of the experimental treatment In that case the negative result of the study would be caused by problems attributable to the implementation and measuring circumstances of the target criteria so that the evaluation of changes cannot be carried out adequately Under the specified evaluation strategy the procedure of measuring the consumption primary outcome measures exclusively by objective methods cannot be maintained
If 5 urine samples are required within a defined period and 2 at most may be positive a deviation of this pattern eg urine samples are missing or cannot be used the patient does not turn up any more prevents that the primary outcome measures can be reliably investigated and documented If this happens at T12 a compensation with data at T6 is possible LOCF It must be assumed however that dropouts occur most often during the first weeks days or even immediately before the beginning of treatment so that a great number of patients never reaches point T6 for the necessary objective measuring therefore it is not realistic to summon dropouts for urine samples 5 times with weekly intervals during the 6th and the 12th month
An increase of cocaine use is proven by hair analyses HA It must be expected also in this case that for various reasons a certain number of patients though much less will not provide a hair sample at T6 or T12
Therefore missing or not useable data concerning the primary outcome measures of illicit heroin use VB1 and cocaine use VB2 respectively will be compensated by the patients report on his consumption during the last 30 days This procedure is as objective as possible results are only compensated by subjective data in exceptional cases dropouts incorrect or missing data
The general treatment response is shown by an improvement of the state of health physical or mental symptoms and by a decrease of illicit heroin consumption as well as by the non-increase of cocaine consumption between the beginning of treatment and the conclusion of phase 1 of the study
B55 Safety Serious adverse events SUE adverse events UE and side effects UAW must be recorded consistently throughout the study Side effects will be investigated quantitatively At each investigation following effects and side effects related to intoxication will be examined routinely
The blood controls carried out within the study will be checked for laboratory test abnormalities Such changes will be documented in the CRF and added to the adverse events UE and if applicable to the unwanted side effects UAW
B6 STATISTICAL ANALYSES B61 Safety analysis Under inclusion of all persons who have been randomised an analysis of emergencies adverse events UE and serious adverse events SUE will be carried out With regard to such events prevalence severity classification potential group differences will be checked for statistical significance
B62 Efficacy analysis The primary outcome analysis will be carried out according to the intention to treat principle ITT which includes all randomised patients ie all patients who were assigned to one of the treatment groups after twice repeated written consent With regard to the 4 x 2-branched study design a 4-factorial logistic regression model will be used In case of missing information the last observation carried forward method LOCF will be applied
Primary outcome analysis For the experimental and the control groups this proof of superiority of heroin will be furnished by a 4-factorial logistic regression model two separated analyses will be calculated for the criterion improvement of the state of health A and for the criterion reduction of illicit drug consumption B
An overall success of the study proof of the superiority of heroin treatment compared to methadone treatment is assumed if both for the main target criterion A improvement of the state of health and the main target criterion B reduction of illicit drug consumption a superiority of heroin treatment in comparison to methadone treatment can be proven in the respective logistic regression model with an α-error of 5
Primary outcome criterion A - Improvement of the state of health
H0A OR 1 Response rate in heroin treatment Response rate in methadone treatment H1A OR 1 Response rate in heroin treatment Response rate in methadone treatment
The hypothesis is tested one-tailed with a 25 alpha error level
Primary outcome criterion B - reduction of illicit drug consumption
H0B OR 1 Rate of illegal drug use in heroin treatment in methadone treatment H1B OR 1 Rate of illegal drug use in heroin treatment in methadone treatment
This hypothesis is also tested one-tailed with a 25 alpha error level
Proof of the overall effect of heroin treatment
The experimental treatment controlled heroin treatment will be rated to be successful if the logistic regression has following results
a response rate for the outcome criterion improvement of the state of health A significantly higher in comparison with the control treatment methadone maintenance AND
a response rate for the outcome criterion reduction of illicit drug consumption B significantly higher in comparison with the control treatment methadone maintenance
Secondary outcome analyses The secondary evaluations are carried out according to the scale levels of the variables or of the indices formed maintenance rate drug consumption scene contacts delinquency housing situation social contacts quality of life mortality rate i e by bivariate or multivariate analyses
B63 Sample size determination
The calculation of the sample size is based on following efficacy expectation
Primary outcome criterion A - improvement of the state of health Efficacy expectation in control groups 30 of responders Efficacy expectation in experimental groups 50 of responders
Primary outcome criterion B - reduction of illicit drug consumption Efficacy expectation in control groups 30 of responders Efficacy expectation in experimental groups 50 of responders Within the framework of the 4 x 2-branched study design each primary outcome criterion will be analysed by a 4-factorial logistic regression analysis With the conservative assumption that both target criteria are stochastically independent a power of 90 for each main outcome criterion guarantees that a multiple total power of 80 is maintained 1-β2 080 for β 010 Since the total success of the study is only assumed if treatment effects are evident for both primary outcome measures a correction of type-1-error is not necessary
A certain number of patients will prematurely drop-out of treatment and not be included in the evaluation by LOCF because they cannot be reached any more for examinations and interviews These are patients who dropped out prior to T6 or have not started treatment or refused their consent to the investigation of the two primary outcome variables According to the conservative evaluation strategy these patients must be treated as worst cases Therefore the size of the assumed effect decreases in relation to the percentage of these not reached patients in the heroin and methadone group Realistic estimations of these percentages are 10 drop-outs in the methadone group and 5 in the heroin group According to these expected percentages the estimated effect size on which the calculation of the sample size is based is reduced from 03 vs 05 to 0370 vs 0475
Based on this assumption a multiple total power of 80 requires a number of cases of at least N482 test persons for each sample group based on Chi2-test for odds ratio sample size approximation according to Nam 1992 Related to the individual strata this means at least four heroin and four methadone strata with at least 121 patients each are necessary to prove the expected effect with a statistical power of 80 For practical reasons adequate distribution to the study centres increased measuring precision this number is rounded up to N140 resulting in eight strata with a total number of N1120 patients
Under the described conditions this sample size guarantees that in both tests a significant difference between methadone and heroin treatment can be proven with a statistical total power of at least 80
B64 Missing data If data of the 12-months examination are missing and concern the primary outcome criteria and cannot be replaced by the LOCF method a non-fulfillment of the criterion must be assumed which will be interpreted as worst case in the individual case
B65 Drop-outs Patients dropping out of treatment will continue to be included in the investigations and evaluations ITT-analysis According to the LOCF method the latest information of each patient will be used for the analysis if a patient cannot be interviewed at the conclusion of the study As far as the primary outcome criterion of illicit heroin consumption is concerned the 12-month information can only be completed by the investigation at T6 because only the five urine samples in the 6th month of treatment can be tested for illicit heroin by GCMS Similarly a missing hair analysis for cocaine consumption at T12 can only be completed by a hair sample precautiously taken at T6 If no objective measure results of the primary outcome measures illicit heroin and cocaine consumption are available the patients self-report will be included in the analysis
Patients who did not participate in any further investigation after the inclusion in the study are rated as worst case ie not reached patients of the methadone group are rated as success responders and not reached patients of the heroin group as failures non-responders Patients who died in the first phase of the study are rated in the experimental and the control group as non-responders Patients who withdraw their consent after randomisation and do not initiate the study treatment are excluded from the ITT-analysis
Part B - Study phase 1 B11 Clinical hypothesis Compared to maintenance with oral methadone heroin treatment leads to
significant improvement of the physical andor mental state of health
greater reduction of illicit drug use and therefore greater detachment from the drug scene
significant improvement of the social situation
higher retention rate or attachment to treatment in the case of those heroin dependent persons who could not be effectively reached or could not sufficiently profit from methadone maintenance programmes
B12 Primary outcome criteria
Improvement of the physical and mental state of health A AND
Reduction of illicit heroin use and non-increase of cocaine use B B13 Secondary outcome criteria
Retention rate
Reduction of benzodiazepine amphetamine alcohol and other drug use
Reduction of scene contacts of contacts to other drug consumers
Decrease of delinquent behaviour
Stabilisation of housing situation
Establishment of new social contacts
Improvement of quality of life
Mortality rate B2 STUDY DESIGN Phase 1 of the clinical trial consists in a 4 x 2-branched randomised multicentre study The sample is stratified and consists on the one hand of heroin dependent persons in methadone maintenance treatment that do not sufficiently profit from treatment MS and on the other hand of heroin dependent persons who are currently not being treated for their addiction NE Patients of both target groups who meet the admission criteria will be randomised to four arms experimental groups MS-E-C and NE-E-C heroin treatment with concurrent case management experimental groups MS-E-P and NE-E-P heroin treatment with concurrent psychoeducationdrug counseling and control groups MS-K-C and NE-K-C methadone treatment with concurrent case management control groups MS-K-P and NE-K-P methadone treatment with concurrent psychoeducationdrug counseling
B22 Recruitment of patients The period of registration is not part of the individual study period A screening is carried out at registration concerning certain inclusion criteria The patients are given the opportunity of a thorough information concerning the conditions and course of the study
First of all patients are asked to sign their consent to participate in the study This is followed by the indication assessment T-1 by the study physician and the external interview EuropASI Certain particularly medical characteristics are again examined at the beginning of treatment T0
The regionally responsible study physician will decide on the inclusion in the study His decision needs the confirmation of a regional committee of experts
B23 Randomisation The allocation to treatment places of the experimental or control group is carried out according to a randomisation code Randomisation is done separately for both groups MS and NE based on permuted blocks of fixed size
After the evaluation of the indication assessment and the first interview at T-1 patients who have been recruited and who fulfil the inclusion criteria are then asked to give a second consent of participation in the study and the results of randomisation will be communicated to them
B24 Course of the study examinations and times of the investigations The first phase of the clinical trial covers a period of 12 months All questioning is done in a personal interview face to face with the assurance that all information will be confidential
All patients who take part in the interviews receive an expense allowance of Euro 15- for each survey
A hair sample is already taken at the indication examination T-1 This allows taking a hair sample fit for analysis at the beginning of treatment T0 from those patients whose hair was too short at T-1 The CIDI will be carried out after one month of treatment in order to minimise initial influences requiring treatment
In order to determine the use of illicit heroin which is a main target criterion five urine controls will be thoroughly examined by GCMS both in the 6th and the 12th month of treatment
B3 PATIENTS The adequate treatment of the questions posed by this study requires a number of at least 140 patients in each test group 4 experimental and 4 control groups Therefore the sample size for the entire study will be N1120
B31 Inclusion criteria
Patients who fulfil following criteria can be included in the study
Minimum age 23 years
Opiate dependence for at least 5 years
Current main diagnosis of opiate dependency according to the ICD-10 criteria
Current daily and predominantly intravenous heroin use or continuing heroin use in maintenance treatment
Symptoms of physical illness indicating a poor state of health according to the OTI health scale at least 13 current symptoms must be found OR Current mental symptoms or disturbances ie a standardised GSI value of the SCL-90-R of at least 60 points
No participation in an addiction treatment programme aa maintenance inpatient or outpatient treatment at least within the last 6 months but documented previous experience with drug therapies OR Negative course of maintenance treatment according to the guidelines of the German Medical Council due to a continuous additional use of heroin 50 of the urine samples positive within the last 6 months or cocaine harmful use of cocainecrack according to ICD-10 in a documented maintenance period of at least 6 months with a current maintenance dose of at least 60 mg d l methadone or 30 mg levomethadone daily
Residence in the city or city state or region for at least 12 months
Voluntary participation and ability to comply with the treatment conditions
Written consent to comply with the treatment conditions B32 Exclusion criteria
Persons with at least one of the following criteria cannot be included in the study
Persons who are currently in prison or awaiting trial or who can be expected to be taken into custody within the next 3 months
Persons who had voluntary phases of abstinence of at least 2 months during the last 12 months
Known epilepsy or generalised convulsions during the last 12 months
Hypersensitivity to test substances and additives
Regular intake of MAO inhibitors
Serious bronchial asthma COPD Cor pulmonale
Serious cardiac arrhythmia
Prostatic hypertrophy with urinary retention
Urethral stricture
Life threatening liver disorders exogenous hepatic coma
Serious renal disorders
Insulin dependent diabetes mellitus
Diagnosed malignancies during the last 6 months
Pregnant women or nursing mothers
Patients unable to comply with the study conditions ie participation in the therapeutic and scientific programmes due to serious physical or mental illness
Patients who are currently participating in another clinical study concerned with the evaluation of an addiction treatment programme
B33 Dropping out of treatment
Participation in the study is voluntary ie the patient can withdraw his consent to be treated and to further participation in the study at any time Patients having at least one of the following characteristics are removed from treatment
Patients suffering from serious somatic complications in connection with heroin or methadone treatment for whom a continuation of treatment would be irresponsible in the opinion of the test study physician and the safety board
Patients with abnormally changed laboratory values for whom a continuation of treatment would incur great health risks according to the safety boards decision
Patients who have not turned up at the treatment centre or who have discontinued the study medication for a period of 14 days or longer for self-provoked reasons or without giving reasons
Patients who are taken into custody for one month or longer
Heroin patients whose treatment must be discontinued for more than 3 months due to hospitalisation or other special treatments
Patients who in the opinion of the study physician cannot or do not want to comply with the conditions of the model project any longer ie participation in the therapeutic and scientific programme
In case of violence threat of violence against persons involved in the project or other patients
In case of drug trafficking on the premises of the model project
In case of theft passing on or sale of prescribed substances B4 TREATMENT B41 Treatment setting Patients will be treated in an outpatient clinic The setting is based on at least weekly contacts to the treating physician Detailed physical examinations and blood counts 10 ml for each withdrawal take place at the start of treatment and after 1 3 6 and 12 months There will be weekly urine analyses qualitative proofs In addition a hair sample will be taken from an inconspicuous place at the back of the head at the beginning of treatment at admission after 6 months and at the examination after 12 months Patients under the influence of alcohol barbiturates or benzodiazepines can be refused their heroin or methadone dose If excessive alcohol consumption is suspected smell of alcohol a breath test is undertaken If the breath test is above 01 heroin or methadone will be refused
B43 Dose regimen Heroin in combination with methadone An additional medication of d-1 methadone at night will be offered from the start ie on the second day of treatment at the earliest The administration of heroin will occur up to 3 times a day during the opening hours of the setting in the morning at noon and in the evening In accordance with the Swiss and Dutch studies the maximum daily dose of iv heroin will be 1000 mg the single dose 400 mg If methadone is claimed at night it can be taken on the premises during the evening opening hours or taken out as a drinkable not injectable single dose The daily maximum dose of additionally prescribed dl methadone should not exceed 60 mg Methadone consumption will be controlled by regular urine analyses
Heroin will be handed out as injectable single doses in filled syringes and administered by the patient himself under observation Patients should stay in the centre for at least 30 minutes after the injection in order to control for possible unwanted effects
The different dose regimens dose regulation at the beginning of treatment or after interruptions starting from different points fading out in case of un-planned treatment conclusions are based on methadone daily equivalence doses MTQ According to the basic rule of the different dose regimens an individual dose of iv heroin for one day alone or in combination with oral methadone must not exceed the MTQ of the previous day by more than 50
Methadone Oral methadone will be administered once a day It is taken on the premises under observation as drinkable not injectable single dose There is no fixed maximum daily dose according to experience dosages between 40 and 160 mgd of methadone in individual cases up to 250 mgd must be expected A 1 methadone HCL solution is recommended
Dose regimen at the conclusion of treatment The conclusion of treatment is done by a step-by-step discontinuation of iv heroin or change to oral methadone The discontinuation of medication iv heroin alone or in combination with methadone will be done slowly Preferably the reduction should not be more than 10-20 of the MTQ of the previous day In most cases discontinuation can be completed within 2 weeks Possible withdrawal symptoms can be treated by concomitant medication
B5 VARIABLES B51 General patient characteristics General and specific sample characteristics such as gender age length of opiate dependency number of previous treatments current social situation are documented
B52 Medical examination and prescription data laboratory parameters The daily amounts of heroin or methadone handed out are registered and all further prescriptions are documented Medical examinations are documented in the CRF
B53 Pharmacokinetics Since pharmacokinetics the analgetic effects the tolerance effects and the addiction potential of heroin are well known and new findings are not to be expected within the framework of this study the study focuses mainly on questions concerning the effects and safety of medication
B54 Efficacy Primary outcome variables Efficacy is investigated with regard to two primary outcome measures - improvement of the state of health A and reduction of illicit drug consumption B These criteria will be evaluated independently by the statistical comparative analysis the success of one treatment in comparison to the other treatment is only proven if both analyses have significant results pointing in the same direction
State of health A
A1 Physical state of health
Number of symptoms according to the health scale of the Opiate Treatment Index OTI at T 1 and T12
VA1n OTI-Health Scale 0 VA1n 50
A2 Mental state of health
Global Severity Index GSI of the SCL-90-R at T 1 and T12 VA2n GSI value 0 VA2n 4
The treatment response concerning the improvement of the state of health is given if one of the two criteria VA1 or VA2 shows an improvement and the other criteria shows no aggravation Improvement and aggravation are defined as follows
For the physical state of health VA1 An improvement is indicated by a decrease on the OTI health scale by at least 20 and at least 4 points if T12 is compared with T-1 an aggravation is an increase of at least 20
For the mental state of health VA2 An improvement is indicated by a decrease of the GSI value by at least 20 if T12 is compared with T-1 an aggravation is an increase of at least 20
Illicit drug consumption B
B1 Use of illicit heroin
Number of illicit heroin-positive urine analyses during the 12 months of treatment ie among the last 5 urine samples before T12
VB1n number of positive urine samples 0 VB1 5 If the patient has dropped out of treatment and results at T12 are missing and the LOCF procedure is not possible because of missing urine samples in the 6th month of treatment but if at least one follow-up has occurred within the ITT method the patients self-reported data on use of illicit heroin physician-CRF will be used If these are also missing self-reported data from the external interview can be used This will be based on the number of days with illicit heroin consumption during the last 30 days VB1 before the corresponding time of investigation
VB1n number of illicit heroin consumption days 0 VB1 30
B2 Cocaine use
Cocaine concentration of hair based on hair analyses HAs at T-1 and T12 within following proof limits
VB2 n cocaine concentration VB2 n 1 μgg If the patient has dropped out of treatment if results at T12 are missing and the LOCF procedure is not possible because of missing HA at T6 but if at least one follow-up has occurred within the ITT method the patients self-reported data on cocaine consumption physician-CRF will be used If these are also missing self-reported data from the external interview can be used This will be based on the number of days with cocaine use during the last 30 days VB2 before the corresponding time of investigation
VB2n number of cocaine consumption days 0 VB2 30 HA does not represent the frequency but the integral intensity within the past period of observation assuming an average hair growth of 10 mm per month The lower limit of proof is assumed to be 1μgg An increase of cocaine consumption can be accurately proven if the value at T12 has increased by 30 in comparison to T-1 If the hair is too short - less than 15 cm - to take a sample at T-1 it will be done at T0
Decrease and non-increase of consumption are defined as follows
A decrease of illicit heroin use is assumed to be proven if not more than 2 of the 5 urine samples tested by GCMS by the 12th month of treatment are positive If only 4 urine samples are available by the 12th month of treatment only one urine sample may be positive to illicit heroin If only 3 urine samples are available none may be positive to illicit heroin in order to be rated as response If fewer urine samples are available by the 12th month of treatment the analyses at the 6th month will be used LOCF proceeding according to the same evaluation pattern Only if no usable urine analyses of the 6th month of treatment exist the patients self-report will be used VB1 A reduction of illicit heroin consumption of at least 60 between T-1 and T12 in relation to the number of consumption days during the last 30 days is rated as a response
The non-increase of cocaine use is proven by the provable cocaine concentration in the hair If a HA cannot be carried out at T12 the hair sample at T6 will be used LOCF Only if a usable HA is neither available at T6 due to a premature discontinuation of treatment the patients self report VB2 will be used A decrease or no change with a tolerance of 2 days of the number of consumption days within the last 30 days between T-1 and T12 is rated as a response Ie an increase of the number of days with cocaine consumption during the last month of not more than 2 days compared to T-1 is still rated as a response only an increase at T12 by more than 2 days is rated as non-response
It has to be assumed that a certain number of patients will prematurely before initiation of treatment or within the first 3 months drop-out of treatment in the case of methadone about 20 up to 40 in the case of heroin 10-20 but that they can be reached again for the examinations and investigations These patients can be summoned for examination at the fixed times but 5 urine samples during the last month will not be available from them These patients without valid data are rated as non-responders in the heroin group and as worst case responders in the methadone group Thus because a rather high percentage of dropouts in the control group have to be expected it would be hardly possible to prove the superiority of the experimental treatment In that case the negative result of the study would be caused by problems attributable to the implementation and measuring circumstances of the target criteria so that the evaluation of changes cannot be carried out adequately Under the specified evaluation strategy the procedure of measuring the consumption primary outcome measures exclusively by objective methods cannot be maintained
If 5 urine samples are required within a defined period and 2 at most may be positive a deviation of this pattern eg urine samples are missing or cannot be used the patient does not turn up any more prevents that the primary outcome measures can be reliably investigated and documented If this happens at T12 a compensation with data at T6 is possible LOCF It must be assumed however that dropouts occur most often during the first weeks days or even immediately before the beginning of treatment so that a great number of patients never reaches point T6 for the necessary objective measuring therefore it is not realistic to summon dropouts for urine samples 5 times with weekly intervals during the 6th and the 12th month
An increase of cocaine use is proven by hair analyses HA It must be expected also in this case that for various reasons a certain number of patients though much less will not provide a hair sample at T6 or T12
Therefore missing or not useable data concerning the primary outcome measures of illicit heroin use VB1 and cocaine use VB2 respectively will be compensated by the patients report on his consumption during the last 30 days This procedure is as objective as possible results are only compensated by subjective data in exceptional cases dropouts incorrect or missing data
The general treatment response is shown by an improvement of the state of health physical or mental symptoms and by a decrease of illicit heroin consumption as well as by the non-increase of cocaine consumption between the beginning of treatment and the conclusion of phase 1 of the study
B55 Safety Serious adverse events SUE adverse events UE and side effects UAW must be recorded consistently throughout the study Side effects will be investigated quantitatively At each investigation following effects and side effects related to intoxication will be examined routinely
The blood controls carried out within the study will be checked for laboratory test abnormalities Such changes will be documented in the CRF and added to the adverse events UE and if applicable to the unwanted side effects UAW
B6 STATISTICAL ANALYSES B61 Safety analysis Under inclusion of all persons who have been randomised an analysis of emergencies adverse events UE and serious adverse events SUE will be carried out With regard to such events prevalence severity classification potential group differences will be checked for statistical significance
B62 Efficacy analysis The primary outcome analysis will be carried out according to the intention to treat principle ITT which includes all randomised patients ie all patients who were assigned to one of the treatment groups after twice repeated written consent With regard to the 4 x 2-branched study design a 4-factorial logistic regression model will be used In case of missing information the last observation carried forward method LOCF will be applied
Primary outcome analysis For the experimental and the control groups this proof of superiority of heroin will be furnished by a 4-factorial logistic regression model two separated analyses will be calculated for the criterion improvement of the state of health A and for the criterion reduction of illicit drug consumption B
An overall success of the study proof of the superiority of heroin treatment compared to methadone treatment is assumed if both for the main target criterion A improvement of the state of health and the main target criterion B reduction of illicit drug consumption a superiority of heroin treatment in comparison to methadone treatment can be proven in the respective logistic regression model with an α-error of 5
Primary outcome criterion A - Improvement of the state of health
H0A OR 1 Response rate in heroin treatment Response rate in methadone treatment H1A OR 1 Response rate in heroin treatment Response rate in methadone treatment
The hypothesis is tested one-tailed with a 25 alpha error level
Primary outcome criterion B - reduction of illicit drug consumption
H0B OR 1 Rate of illegal drug use in heroin treatment in methadone treatment H1B OR 1 Rate of illegal drug use in heroin treatment in methadone treatment
This hypothesis is also tested one-tailed with a 25 alpha error level
Proof of the overall effect of heroin treatment
The experimental treatment controlled heroin treatment will be rated to be successful if the logistic regression has following results
a response rate for the outcome criterion improvement of the state of health A significantly higher in comparison with the control treatment methadone maintenance AND
a response rate for the outcome criterion reduction of illicit drug consumption B significantly higher in comparison with the control treatment methadone maintenance
Secondary outcome analyses The secondary evaluations are carried out according to the scale levels of the variables or of the indices formed maintenance rate drug consumption scene contacts delinquency housing situation social contacts quality of life mortality rate i e by bivariate or multivariate analyses
B63 Sample size determination
The calculation of the sample size is based on following efficacy expectation
Primary outcome criterion A - improvement of the state of health Efficacy expectation in control groups 30 of responders Efficacy expectation in experimental groups 50 of responders
Primary outcome criterion B - reduction of illicit drug consumption Efficacy expectation in control groups 30 of responders Efficacy expectation in experimental groups 50 of responders Within the framework of the 4 x 2-branched study design each primary outcome criterion will be analysed by a 4-factorial logistic regression analysis With the conservative assumption that both target criteria are stochastically independent a power of 90 for each main outcome criterion guarantees that a multiple total power of 80 is maintained 1-β2 080 for β 010 Since the total success of the study is only assumed if treatment effects are evident for both primary outcome measures a correction of type-1-error is not necessary
A certain number of patients will prematurely drop-out of treatment and not be included in the evaluation by LOCF because they cannot be reached any more for examinations and interviews These are patients who dropped out prior to T6 or have not started treatment or refused their consent to the investigation of the two primary outcome variables According to the conservative evaluation strategy these patients must be treated as worst cases Therefore the size of the assumed effect decreases in relation to the percentage of these not reached patients in the heroin and methadone group Realistic estimations of these percentages are 10 drop-outs in the methadone group and 5 in the heroin group According to these expected percentages the estimated effect size on which the calculation of the sample size is based is reduced from 03 vs 05 to 0370 vs 0475
Based on this assumption a multiple total power of 80 requires a number of cases of at least N482 test persons for each sample group based on Chi2-test for odds ratio sample size approximation according to Nam 1992 Related to the individual strata this means at least four heroin and four methadone strata with at least 121 patients each are necessary to prove the expected effect with a statistical power of 80 For practical reasons adequate distribution to the study centres increased measuring precision this number is rounded up to N140 resulting in eight strata with a total number of N1120 patients
Under the described conditions this sample size guarantees that in both tests a significant difference between methadone and heroin treatment can be proven with a statistical total power of at least 80
B64 Missing data If data of the 12-months examination are missing and concern the primary outcome criteria and cannot be replaced by the LOCF method a non-fulfillment of the criterion must be assumed which will be interpreted as worst case in the individual case
B65 Drop-outs Patients dropping out of treatment will continue to be included in the investigations and evaluations ITT-analysis According to the LOCF method the latest information of each patient will be used for the analysis if a patient cannot be interviewed at the conclusion of the study As far as the primary outcome criterion of illicit heroin consumption is concerned the 12-month information can only be completed by the investigation at T6 because only the five urine samples in the 6th month of treatment can be tested for illicit heroin by GCMS Similarly a missing hair analysis for cocaine consumption at T12 can only be completed by a hair sample precautiously taken at T6 If no objective measure results of the primary outcome measures illicit heroin and cocaine consumption are available the patients self-report will be included in the analysis
Patients who did not participate in any further investigation after the inclusion in the study are rated as worst case ie not reached patients of the methadone group are rated as success responders and not reached patients of the heroin group as failures non-responders Patients who died in the first phase of the study are rated in the experimental and the control group as non-responders Patients who withdraw their consent after randomisation and do not initiate the study treatment are excluded from the ITT-analysis
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None