Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001088437p
Ethics application status
Submitted, not yet approved
Date submitted
2/08/2016
Date registered
12/08/2016
Date last updated
12/08/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Does locally produced Enalapril (Envas) work as well as imported Enalapril (EnaDenk) in the treatment of individual patients with hypertension? Addis Ababa, Ethiopia
Scientific title
A series of N-of-1 trials to assess therapeutic interchangeability of two Enalapril formulations in the treatment of hypertension, Addis Ababa, Ethiopia
Secondary ID [1] 289822 0
Nil
Universal Trial Number (UTN)
U1111-1185-9747
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypertension 299748 0
Condition category
Condition code
Cardiovascular 299680 299680 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Drug: Locally produced Enalapril-Envas (Cadila pharmaceutical, Ethiopia)
Dose: 5-20mg. Participants in this study are those whose blood pressure is controlled with Enalapril. Therefore, participants will continue on the dose that they are currently taking for the duration of the trial. For example, if the patient is taking 10mg, she/he will continue taking the same dose. The dose determination and follow up during the study will be made by the treating physician.
Frequency: once daily in the morning
Duration: There are 3 pairs of treatment periods. Each pair of treatment period comprises 1 week of Envas and 1 week of EnaDenk -treatment crossover occurs weekly. Individual patients will take Envas for 3 treatment periods of 1 week each.
Mode: Per oral
Adherence monitoring : To avoid treatment non-compliance, every week, there will be a drug adherence counselling session by the study nurse before drug dispensing. Moreover, every week, the study nurse will check pill boxes and ask questions if there are missed medications.
Washout period: Participants will move straight on from treatment period 1 to treatment period 2 on consecutive days. To account for washout from the previous period, the first two days of BP readings in each treatment period will be discarded i.e. two days analytical washout period.
Intervention code [1] 295498 0
Treatment: Drugs
Comparator / control treatment
Drug: Imported Enalapril-EnDenk (PharmaDenk, German)
Dose: 5-20mg. Participants in this study are those whose blood pressure is controlled with Enalapril. Therefore, participants will continue on the dose that they are currently taking for the duration of the trial. For example, if the patient is taking 10mg, she/he will continue taking the same dose. The dose determination a nd follow up during the study will be made by the treating physician.
Frequency: once daily in the morning
Duration: There are 3 pairs of treatment periods. Each pair of treatment period comprises 1 week of Envas and 1 week of EnaDenk -treatment crossover occurs weekly. Individual patients will take EnaDenk for 3 treatment periods of 1 week each.
Mode: Per oral
Control group
Active

Outcomes
Primary outcome [1] 299144 0
Primary outcome: Mean home Systolic BP difference
Outcome assessment: Individual participants will record their blood pressure two times (morning and evening) daily using BP recording diary.
BP will be measured using automated BP monitoring devise.
Timepoint [1] 299144 0
This is a therapeutic equivalence trial designed to assess interchangeablity of two Enalapril formulations. Outcome will be assessed using home blood pressure readings which are taken twice daily (morning and evening) for each of the 3 (2x 1 week) treatment cycles. Outcome will be assessed 6 weeks after intervention commencement. Interchangeablity will be established if equivalence is evident in at least in two cycles out of three.
Secondary outcome [1] 326314 0
Change in mean home DBP for both evening and morning diastolic BP values
Individual participants will record their blood pressure two times (morning and evening) daily using BP recording diary.
BP will be measured using automated BP monitoring devise.

Timepoint [1] 326314 0
Outcome will be assessed using home blood pressure readings which are taken twice daily (morning and evening) for each of the 3 (2x 1 week) treatment cycles. Outcome will be assessed 6 weeks after intervention commencement.
Secondary outcome [2] 326367 0
Change in mean clinic DBP.
The study physician will assess the patient before and after each treatment period (each week) and measure BP using auscultatory BP device.
Timepoint [2] 326367 0
Clinic blood pressure readings will be taken once/day at baseline and weekly throughout each of the 3 (2x 1 week) treatment cycles. Outcome will be assessed 6 weeks after intervention commencement.
Secondary outcome [3] 326368 0
Change in mean clinic SBP.
The study physician will assess the patient before and after each treatment period (each week) and measure BP using auscultatory BP device.
Timepoint [3] 326368 0
Clinic blood pressure readings will be taken once/day at baseline and weekly throughout each of the 3 (2x 1 week) treatment cycles. Outcome will be assessed 6 weeks after intervention commencement.
Secondary outcome [4] 326369 0
Change in mean home DBP measured in the morning, 24 hours after drug intake.
Individual participants will record their blood pressure two times (morning and evening) daily using BP recording diary.
BP will be measured using automated BP monitoring devise.
Timepoint [4] 326369 0
Home blood pressure readings will be taken once daily (morning), 24 hours following every drug dose for each of the 3 (2x 1 week) treatment cycles. Outcome will be assessed 6 weeks after intervention commencement.
Secondary outcome [5] 326370 0
Change in mean home DBP measured in the evening, 12 hours after drug intake.
Individual participants will record their blood pressure two times (morning and evening) daily using BP recording diary.
BP will be measured using automated BP monitoring devise.
Timepoint [5] 326370 0
Home blood pressure readings will be taken once daily (evening), 12 hours following every drug dose for each of the 3 (2x 1 week) treatment cycles. Outcome will be assessed 6 weeks after intervention commencement.
Secondary outcome [6] 326371 0
Change in mean home SBP measured in the evening, 12 hours after drug intake.
Individual participants will record their blood pressure using BP recording diary.
BP will be measured using automated BP monitoring devise.
Timepoint [6] 326371 0
Home blood pressure readings will be taken once daily (evening), 12 hours following every drug dose for each of the 3 (2x 1 week) treatment cycles. Outcome will be assessed 6 weeks after intervention commencement.
Secondary outcome [7] 326372 0
Change in mean home SBP measured in the morning, 24 hours after drug intake.
Individual participants will record their blood pressure two times (morning and evening) daily using BP recording diary.
BP will be measured using automated BP monitoring devise.
Timepoint [7] 326372 0
Home blood pressure readings will be taken once daily (morning), 24 hours following every drug dose for each of the 3 (2x 1 week) treatment cycles. Outcome will be assessed 6 weeks after intervention commencement.
Secondary outcome [8] 326373 0
Study feasibility as measured by
1. Enrolement rate: the proportion of eligible participants who are enrolled and;
2. Completion rate: the proportion of enrolled participants who completed the trial. The primary investigator will collect data using feasibility assessment checklist.
Timepoint [8] 326373 0
Enrolment rate will be assessed one day after enrolment (after participants take their first dose). Completion rate will be assessed 6 weeks after intervention commencement.
Secondary outcome [9] 326374 0
Safety outcome e.g. dry cough, syncope, dizziness.
Individual patients will collect side effects using an open-ended side effect questionnaire designed for this study.
Timepoint [9] 326374 0
Safety will be assessed 6 weeks after intervention commencement.

Eligibility
Key inclusion criteria
1. Male and female patients with primary hypertension controlled on Enalapril/Enalapril containing regimen- those who have achieved a blood pressure target of 140/90 mmHg or less in at least the last 2 months (clinic readings)
2. Subjects who are between 18 – 80 years of age
3. Serum electrolytes and creatinine within the normal range (or the clinical investigator considers the deviation to be irrelevant for the purpose of the study)
4. Normal ECG or stable abnormalities which the clinical investigator does not consider a disqualification for participation in the study
5. Willingness to undergo a pre-study physical examination and laboratory investigations
6. Ability to comprehend and willingness to sign statement of informed consent
7. Women of child bearing potential having effective contraception in place. If this is oral contraception, then they should have been on it at least 2 months.
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Any evidence of clinically significant, poorly controlled hematologic, renal, hepatic, or gastrointestinal problems (current thrombocytopenia (platelet count < 100 ×109/L or hemoglobin < 10 g/dL); liver function test abnormalities (alanine aminotransferase or aspartate aminotransferase greater than or equal to' upper limit of normal [ULN]) or severe renal dysfunction (creatinine clearance < 25 mL/min)
2. Any evidence within the last six months of clinically significant diseases involving the cerebrovascular, autoimmune, or cardiovascular systems, including poorly controlled angina pectoris, secondary hypertension, congestive heart failure, or myocardial infarction or stroke.
3. Concomitant use of major psychotropic agents or antidepressant drugs or regular use of nonsteroidal anti-inflammatory agents, high-dose aspirin, or any agent that could raise or lower blood pressure within the last 2 months.
4. A history of drug or alcohol abuse.
5. Sensitivity to angiotensin-converting enzyme (ACE) inhibitors,
6. Unwillingness to follow the study protocol or study-related procedures (e.g. swallow tablets).
7. Clinically significant abnormal ECG findings or vital signs during screening.
8. Clinically significant illness or surgery within 4 weeks prior to study.
9. Pregnant (positive pregnancy test) or breast-feeding women or women who are planning to be pregnant during the trial period.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be concealed using central randomisation by computer. A statistician at the university will manage this procedure.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
We will use block randomization
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?

The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
This is an individual pilot N-of-1 trial. Analysis and outcome report will be made for each patient. Sample size calculation is not required to assess outcome of interest. However, the number of observations taken in each treatment period is important. Every day, Patients will take six BP measurements (3 in the morning and 3 in the evening) at home.
To assess the success of this pilot study, a total of 30 patients will be included. This is made based on literature.
Differences in means will be compared using a paired Student’s t test as appropriate. Significance will be set at P = 0.05. Standard statistical procedures will conducted using the R-package.
Possible side effects of the study medication and any serious adverse events will be tabulated for individual patients.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/01/2017
Actual
Date of last participant enrolment
Anticipated
10/05/2017
Actual
Date of last data collection
Anticipated
30/06/2017
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment outside Australia
Country [1] 8069 0
Ethiopia
State/province [1] 8069 0
Addis Ababa

Funding & Sponsors
Funding source category [1] 294206 0
University
Name [1] 294206 0
University of Queensland
Country [1] 294206 0
Australia
Primary sponsor type
University
Name
University of Queensland
Address
Brisbane St Lucia, QLD 4072

Country
Australia
Secondary sponsor category [1] 293040 0
None
Name [1] 293040 0
Not applicable
Address [1] 293040 0
Not applicable
Country [1] 293040 0
Other collaborator category [1] 279136 0
Government body
Name [1] 279136 0
Armauer Hansen Research Institute (AHRI)
Address [1] 279136 0
Addis Ababa, Jimma Road, P.O. Box 1005
Country [1] 279136 0
Ethiopia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 295614 0
UQ Human Ethics Committee
Ethics committee address [1] 295614 0
Brisbane St Lucia, QLD 4072

Ethics committee country [1] 295614 0
Australia
Date submitted for ethics approval [1] 295614 0
18/07/2016
Approval date [1] 295614 0
Ethics approval number [1] 295614 0
-

Summary
Brief summary
Drugs are originally produced by one pharmaceutical company and are considered to be the perfect comparator products. When the patent expires, other companies can produce a similar product with comparable efficacy and safety. These drugs are called generic drugs. Currently, CADILA Pharmaceuticals Ltd (Ethiopia) produce the Enalapril (Envas) in Ethiopia. However, to ensure its effectiveness, the comparative efficacy and safety of this drug against the original products should be tested.. Currently, appropriate tests (bioequivalence tests) to prove effectiveness are not available in Ethiopia.
Many patients with hypertension take Enalapril to control their blood pressure. Using locally produced Enalapril is a cheaper option for patients with hypertension. However, as mentioned above, there is no evidence that proves that locally produced Enalapril works as well as the original (standard) Enalapril. The aim of the trial is to test whether locally produced Enalapril works as well as imported Enalapril in the treatment of hypertension.
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 992 992 0 0
/AnzctrAttachments/371219(v04-08-2016-17-45-14)-Envas-EnaDenk N-of-1 Trial -Vn 3.0-(01.08.16).docx

Contacts
Principal investigator
Name 67934 0
Mr Chalachew Alemayehu
Address 67934 0
School of Medicine, University of Queensland
288 Herston Road
Herston QLD 4006
Australia
Country 67934 0
Australia
Phone 67934 0
+61-405711632
Fax 67934 0
-
Email 67934 0
c.alemayehu@uq.edu.au
Contact person for public queries
Name 67935 0
Mr Chalachew Alemayehu
Address 67935 0
School of Medicine, University of Queensland
288 Herston Road
Herston QLD 4006
Australia
Country 67935 0
Australia
Phone 67935 0
+61-405711632
Fax 67935 0
-
Email 67935 0
c.alemayehu@uq.edu.au
Contact person for scientific queries
Name 67936 0
Mr Chalachew Alemayehu
Address 67936 0
School of Medicine, University of Queensland
288 Herston Road
Herston QLD 4006
Australia
Country 67936 0
Australia
Phone 67936 0
+61-405711632
Fax 67936 0
-
Email 67936 0
c.alemayehu@uq.edu.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseA series of N-of-1 trials to assess the therapeutic interchangeability of two enalapril formulations in the treatment of hypertension in Addis Ababa, Ethiopia: Study protocol for a randomized controlled trial.2017https://dx.doi.org/10.1186/s13063-017-2212-0
N.B. These documents automatically identified may not have been verified by the study sponsor.