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Evaluation of the Safety of Primaquine in Combination With Dihydroartemisinin-piperaquine in G6PD Deficient Males in The Gambia (SAFEPRIM-II)

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ClinicalTrials.gov Identifier: NCT02654730
Recruitment Status : Terminated (Enrollment took longer than anticipated; it was financially and logistically impossible to recruit the final cohort (G6PDd 0.4mg/kg PQ).)
First Posted : January 13, 2016
Last Update Posted : September 9, 2016
Sponsor:
Collaborator:
Medical Research Council Unit, The Gambia
Information provided by (Responsible Party):
London School of Hygiene and Tropical Medicine

Tracking Information
First Submitted Date  ICMJE January 5, 2016
First Posted Date  ICMJE January 13, 2016
Last Update Posted Date September 9, 2016
Study Start Date  ICMJE December 2015
Actual Primary Completion Date September 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 11, 2016)
Haemoglobin concentration relative to baseline value as measured by HemoCue [ Time Frame: 28 days ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02654730 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 11, 2016)
  • Haematology abnormalities during follow-up: haptoglobin concentration measured in venous blood samples by full blood count analysis [ Time Frame: 28 days ]
  • Biochemistry abnormalities during follow-up: bilirubin concentration [ Time Frame: 28 days ]
  • Biochemistry abnormalities during follow-up: lactate dehydrogenase [ Time Frame: 28 days ]
  • Biochemistry abnormalities during follow-up: creatinine [ Time Frame: 28 days ]
  • Biochemistry abnormalities during follow-up: potassium [ Time Frame: 28 days ]
  • Number of participants with treatment-related adverse events graded and evaluated in terms of relatedness [ Time Frame: 28 days ]
    grading and assessing relatedness will be done following according to criteria of the NIH/NIAID division of microbiology and infectious diseases (DMID)https://www.niaid.nih.gov/LabsAndResources/resources/DMIDClinRsrch/Documents/dmidadulttox.pdf
  • Haematology abnormalities during follow-up: mean corpuscular volume (MCV) measured in venous blood samples by full blood count analysis [ Time Frame: 28 days ]
  • Haematology abnormalities during follow-up: red cell distribution width (RDW) measured in venous blood samples by full blood count analysis [ Time Frame: 28 days ]
  • Haematology abnormalities during follow-up: leukocyte count measured in venous blood samples by full blood count analysis [ Time Frame: 28 days ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluation of the Safety of Primaquine in Combination With Dihydroartemisinin-piperaquine in G6PD Deficient Males in The Gambia
Official Title  ICMJE Evaluation of the Safety of Primaquine in Combination With Dihydroartemisinin-piperaquine in G6PD Deficient Males in The Gambia
Brief Summary The purpose of this study is to evaluate the tolerability and safety of increasing doses of primaquine in combination with dihydroartemisinin-piperaquine in G6PD deficient males.
Detailed Description

In the current study the investigators aim to assess safety of PQ, in particular the risk of acute haemolysis, when given together with dihydroartemisinin-piperaquine (DHAP) in G6PD deficient individuals. Forty male participants with haemoglobin levels (≥11g/dL), reduced G6PD enzyme function, and aged ≥10years will be sequentially enrolled into two dosing cohorts consisting of 20 individuals and doses of 0.25 and 0.4 mg/kg PQ in combination with a full three-day course of DHAP. Participants will first be assigned to the lowest open cohort; enrolment in the next cohort is initiated after tolerability and short-term safety is demonstrated at the preceding lower dose. Furthermore, the investigators will include 3 control groups into the first cohort: i) 10 male participants aged ≥10years with normal haemoglobin levels (≥11g/dL) and a reduced G6PD enzyme function will receive DHAP only, ii) 10 male participants with normal haemoglobin levels (≥11g/dL) and normal G6PD enzyme function will receive 0.25 mg/kg PQ in combination with a full three-day course of DHAP, and iii) 10 male participants with normal haemoglobin levels (≥11g/dL) and normal G6PD enzyme function will receive 0.4 mg/kg PQ with DHAP.

Enrolment and group assignment Individuals who agree to participate for screening and meet all inclusion criteria, will be invited for enrolment. During this, participants and/or their carers will be informed again about the objectives and practical consequences of participation in the current study and asked to sign an informed consent form. The possibility of withdrawal from the study, at any time and without any declaration of the reason will again be pointed out.

After enrolment, participants will be assigned to the lowest-dose open cohort, with enrolment in the second cohort initiated after tolerability and short-term safety is demonstrated at the preceding lower dose (this enrolment to the second cohort accounts for G6PD deficient participants only). Within each cohort, the first 2 participants of the intervention group are treated and monitored for 6 days for immediate side-effects and haematological abnormalities before the rest of the participants of that particular intervention group are enrolled and treated. Once safety of these first 2 participants is confirmed, the next 4 subjects are enrolled and treatment for the next 4 subjects is initiated on day 2 of the last treated participant of the preceding 4 subjects. The last two groups for each intervention group comprise 5 individuals, making a total of 20. After inclusion of the intervention group of the first cohort (n=20) is completed (follow-up day 14 of last participant in that group), a 10-day safety observation period is installed before enrolment of the intervention group of the second cohort is initiated.

Interventions and evaluation Clinical follow-up of participants and sampling will be done twice daily for the first 4 days (days 0, 1, 2 and 3) and once daily on days 4, 5, 7, 10, 14 and 28. At each time-point participants will be examined clinically (except for day 28) and a structured questionnaire is used to determine the occurrence of side effects. Furthermore, laboratory safety parameters are measured, including haematology, biochemistry, and urine dipstick for haemoglobinuria/urobilinogen. Five individuals from each intervention group (total of 10) will also be asked to provide seven venous blood samples (of less than 1 mls each) on days 0, 1 and 2 to study pharmacokinetics of PQ in G6PD deficient individuals

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Malaria
Intervention  ICMJE
  • Drug: Dihydroartemisinin-piperaquine (DHAP) administered to G6PD deficient
    G6PD deficient participants will be treated with dihydroartemisinin-piperaquine (Eurartesim®; Sigma Tau) administered as 3 tablets (40mg PPQ, 320mg DHA) in a once daily regimen for three days
    Other Name: Eurartesim
  • Drug: Dihydroartemisinin-piperaquine (DHAP) + 0.25 mg/kg primaquine administered to G6PD deficient
    G6PD deficient participants will be treated with dihydroartemisinin-piperaquine (Eurartesim®; Sigma Tau) administered as 3 tablets (40mg PPQ, 320mg DHA) in a once daily regimen for three days in combination with a single dose of 0.25mg/kg of primaquine on the first day of DHAP treatment.
  • Drug: Dihydroartemisinin-piperaquine (DHAP) + 0.4 mg/kg primaquine administered to G6PD deficient
    G6PD deficient participants will be treated with dihydroartemisinin-piperaquine (Eurartesim®; Sigma Tau) administered as 3 tablets (40mg PPQ, 320mg DHA) in a once daily regimen for three days in combination with a single dose of 0.4mg/kg of primaquine on the first day of DHAP treatment.
  • Drug: Dihydroartemisinin-piperaquine (DHAP) + 0.25 mg/kg primaquine administered to G6PD normal
    G6PD normal participants will be treated with dihydroartemisinin-piperaquine (Eurartesim®; Sigma Tau) administered as 3 tablets (40mg PPQ, 320mg DHA) in a once daily regimen for three days in combination with a single dose of 0.25mg/kg of primaquine on the first day of DHAP treatment.
  • Drug: Dihydroartemisinin-piperaquine (DHAP) + 0.4 mg/kg primaquine administered to G6PD normal
    G6PD normal participants will be treated with dihydroartemisinin-piperaquine (Eurartesim®; Sigma Tau) administered as 3 tablets (40mg PPQ, 320mg DHA) in a once daily regimen for three days in combination with a single dose of 0.4mg/kg of primaquine on the first day of DHAP treatment.
Study Arms  ICMJE
  • Experimental: G6PD deficient 0.25 mg/kg PQ + DHAP
    Intervention: Drug: Dihydroartemisinin-piperaquine (DHAP) + 0.25 mg/kg primaquine administered to G6PD deficient
  • Experimental: G6PD deficient 0.4 mg/kg PQ + DHAP
    Intervention: Drug: Dihydroartemisinin-piperaquine (DHAP) + 0.4 mg/kg primaquine administered to G6PD deficient
  • Active Comparator: G6PD deficient DHAP only
    Intervention: Drug: Dihydroartemisinin-piperaquine (DHAP) administered to G6PD deficient
  • Active Comparator: G6PD normal 0.25 mg/kg PQ + DHAP
    Intervention: Drug: Dihydroartemisinin-piperaquine (DHAP) + 0.25 mg/kg primaquine administered to G6PD normal
  • Active Comparator: G6PD normal 0.4 mg/kg PQ + DHAP
    Intervention: Drug: Dihydroartemisinin-piperaquine (DHAP) + 0.4 mg/kg primaquine administered to G6PD normal
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: September 8, 2016)
61
Original Estimated Enrollment  ICMJE
 (submitted: January 11, 2016)
70
Estimated Study Completion Date  ICMJE December 2016
Actual Primary Completion Date September 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • G6PD deficiency by fluorescent Spot test (for intervention groups and control group receiving DHA-PPQ only (N=50)
  • G6PD normal activity by fluorescent Spot test for control groups (N=20)
  • Informed consent by participant or caregiver (an assent is required for those 12-17 years)

Exclusion Criteria:

  • Enrolled in another clinical trial
  • Fever: temperature >37.5°C (axillary) or history of fever in the last 24 hours
  • Evidence of severe illness or active infection other than malaria
  • Known allergy to study medications
  • Hb <11 g/dL
  • Antimalarials taken within the last 2 weeks
  • PQ taken within the last 4 weeks and blood transfusion within the last 90 days
  • Current use of tuberculosis or anti-retroviral medication, sulphonamides, dapsone, nitrofurantoin, nalidixic acid, ciprofloxacin, methylene blue, toluidine blue, phenazopyridine and co-trimoxazole.
  • History of severe chronic illness
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 10 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Gambia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02654730
Other Study ID Numbers  ICMJE SAFEPRIM-II
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: WWARN
Responsible Party London School of Hygiene and Tropical Medicine
Study Sponsor  ICMJE London School of Hygiene and Tropical Medicine
Collaborators  ICMJE Medical Research Council Unit, The Gambia
Investigators  ICMJE Not Provided
PRS Account London School of Hygiene and Tropical Medicine
Verification Date January 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP