An Evaluation of Weekly Tafenoquine

• Sponsor: U.S. Army Medical Research and Development Command (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT02488980
• Collaborator: SmithKline Beecham (Industry)
• Enrollment: 306
• Arms: 3
• Duration (Months): 34

Study Details

Study Description

Brief Summary

This was a placebo controlled, randomised, double-blind, double-dummy study of the efficacy of weekly tafenoquine compared with weekly mefloquine or placebo in the chemosuppression of

1. falciparum in Nyanza Province, western Kenya.

Condition or Disease	Intervention/Treatment	Phase
Falciparum Parasitaemia	Drug: Tafenoquine; Drug: Mefloquine; Drug: Placebo	Phase 2

Detailed Description

Subjects were treated for 3 days with halofantrine to clear any existing parasitaemia. At the end of the clearance period, subjects free from malaria parasitaemia were randomized and received a loading dose of the study treatment (tafenoquine 200 mg, Mefloquine 250 mg or placebo) for tree days, followed by study treatment (tafenoquine 200 mg, mefloquine 250 mg or placebo, respectively) once a week for 24 weeks. After the treatment period subjects attended weekly follow-up safety visits until week 28.

Study Design

• Study Type: Interventional
• Actual Enrollment: 306 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double Blind, Placebo Controlled Evaluation of Weekly Tafenoquine (WR 238605/SB252263) Compared to Mefloquine for Chemosuppression of Plasmodium Falciparum in Western Kenya
• Study Start Date: May 1, 2000
• Actual Primary Completion Date: Oct 1, 2000
• Actual Study Completion Date: Mar 1, 2003

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tafenoquine Tafenoquine 200 mg for three days followed by Tafenoquine 200 once a week for 24 weeks.	Drug: Tafenoquine; Tafenoquine 200 mg for three days followed by Tafenoquine 200 mg once a week for 24 weeks.
Active Comparator: Mefloquine Mefloquine 250 mg for three days followed by Mefloquine 250 once a week for 24 weeks.	Drug: Mefloquine; Mefloquine 250 mg for three days followed by Mefloquine 250 mg once a week for 24 weeks.
Placebo Comparator: Placebo Placebo	Drug: Placebo; Placebo for three days followed by placebo once a week for 24 weeks

Outcome Measures

Primary Outcome Measures

1. Prophylactic Outcome Defined by the Subject Having no Positive Smears [24 Weeks]

   Prophylactic outcome (success/failure) at the end of the prophylactic treatment phase; outcome was based on absence/presence of asexual stage parasites of any Plasmodium species on a single blood smear.

Secondary Outcome Measures

1. Protective Efficacy Based on Two Consecutive Positive Smears [24 Weeks]

   Kaplan-Meier survival curves were produced for time to parasitaemia for both first positive smear and two consecutive positive smears. Analysis was based on a calculation of protective efficacy (PE) of tefaenoquine, defined as (1-relative risk of developing parasitaemia tafenoquine: placebo) x100% and 95.5% confidence intervals were constructed for the relative risk using Koopman's method.

2. Time to a Single Positive Smear [24 Weeks]

   Kaplan-Meier survival curves were produced for time to parasitaemia for both first positive smear and two consecutive positive smears. 95.5% confidence intervals were constructed for the relative risk.

Other Outcome Measures

1. Safety (SAEs and AEs) [28 weeks]

   The most commonly reported experiences in subject occurring in at least 20% of subjects in any treatment group.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy male or female volunteers who provided informed consent (a healthy volunteer was defined as one who was free of ailments that might cause difficulty in evaluating drug efficacy or adverse experiences).

• Subjects aged 18-55 years.

• Subjects planning to reside in the study area for the entire study duration of approximately 70 weeks

Exclusion Criteria:

• Subjects with positive parasitaemia following halofantrine treatment for radical cure.

• Subjects with any medical condition which, in the opinion of the investigator, made the subject unsuitable to enter the study.

• Subjects with personal or family history of seizures.

• Female subjects with a positive serum beta-HCG5 (tested during screening and within 48 hours of first drug administration and approximately monthly thereafter).

• Women who were pregnant or lactating or who in the opinion of the investigator were at risk of becoming pregnant.

• Subjects with clinically significant abnormalities (to include but not limited to abnormal hepatic or renal function) as determined by history, physical and routine blood chemistries and haematology values. Subjects who had demonstrated hypersensitivity to any of the study drugs especially to any other 8-aminoquinolines.

• Subjects unwilling to report for drug administration or blood drawing during the 70 week duration of the study.

• Subjects with G6PD deficiency.

• Subjects with laboratory guideline values for exclusion: haemoglobin <10 gm/dL, platelets <80,000/mm3, WBC <3000ul3, creatinine or ALT more than twice the upper limit of normal for age.

• Subjects with an abnormal ECG, particularly an extended QTc interval > 0.42 seconds.

• Subjects taking any other anti-malarial product, or who had taken an antimalarial drug other than halofantrine within the previous two weeks.

• Subjects who had received an investigational drug (a new chemical entity not registered for use) within 30 days or 5 half-lives whichever was the longer.

• Subjects with a history of psychiatric disorder.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• U.S. Army Medical Research and Development Command
• SmithKline Beecham

Investigators

• Principal Investigator: Jose Stoute, MD, Penn State Hershey Infectious Diseases

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: U.S. Army Medical Research and Development Command
• ClinicalTrials.gov Identifier: NCT02488980
• Other Study ID Numbers: A-9467
• First Posted: Jul 2, 2015
• Last Update Posted: May 30, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by U.S. Army Medical Research and Development Command: Falciparum Parasitaemia, Malaria
• Additional relevant MeSH terms: Parasitemia; Mefloquine; Tafenoquine

Study Results

Participant Flow

Recruitment Details	This study was conducted at Kombewa Clinic, Kenya. 517 subjects were screened for entry in to the study. 211 of those subjects were not randomized to treatment due either to abnormal lab results, G6PD deficiency, extended QTc interval, failure to clear parasitaemia or "other" reason.

Arm/Group Title	Tafenoquine	Mefloquine	Placebo
Arm/Group Description	Tafenoquine 200 mg for three days followed by Tafenoquine 200 once a week for 24 weeks. Tafenoquine: Tafenoquine 200 mg for three days followed by Tafenoquine 200 mg once a week for 24 weeks.	Mefloquine 250 mg for three days followed by Mefloquine 250 once a week for 24 weeks. Mefloquine: Mefloquine 250 mg for three days followed by Mefloquine 250 mg once a week for 24 weeks.	Placebo Placebo: Placebo for three days followed by placebo once a week for 24 weeks
Period Title: Overall Study
STARTED	104	101	101
COMPLETED	102	99	99
NOT COMPLETED	2	2	2

Baseline Characteristics

Arm/Group Title	Placebo	Tafenoquine	Mefloquine	Total
Arm/Group Description	Placebo Placebo: Placebo for three days followed by placebo once a week for 24 weeks	Tafenoquine 200 mg for three days followed by Tafenoquine 200 once a week for 24 weeks. Tafenoquine: Tafenoquine 200 mg for three days followed by Tafenoquine 200 mg once a week for 24 weeks.	Mefloquine 250 mg for three days followed by Mefloquine 250 once a week for 24 weeks. Mefloquine: Mefloquine 250 mg for three days followed by Mefloquine 250 mg once a week for 24 weeks.	Total of all reporting groups
Overall Participants	99	102	99	300
Age (Count of Participants)
<=18 years	1 1%	2 2%	2 2%	5 1.7%
Between 18 and 65 years	98 99%	100 98%	97 98%	295 98.3%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	36 36.4%	36 35.3%	33 33.3%	105 35%
Male	63 63.6%	66 64.7%	66 66.7%	195 65%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	99 100%	102 100%	99 100%	300 100%
White	0 0%	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Kenya	99 100%	102 100%	99 100%	300 100%

Outcome Measures

1. Primary Outcome

Title	Prophylactic Outcome Defined by the Subject Having no Positive Smears
Description	Prophylactic outcome (success/failure) at the end of the prophylactic treatment phase; outcome was based on absence/presence of asexual stage parasites of any Plasmodium species on a single blood smear.
Time Frame	24 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Tafenoquine	Mefloquine
Arm/Group Description	Placebo Placebo: Placebo for three days followed by placebo once a week for 24 weeks	Tafenoquine 200 mg for three days followed by Tafenoquine 200 once a week for 24 weeks. Tafenoquine: Tafenoquine 200 mg for three days followed by Tafenoquine 200 mg once a week for 24 weeks.	Mefloquine 250 mg for three days followed by Mefloquine 250 once a week for 24 weeks. Mefloquine: Mefloquine 250 mg for three days followed by Mefloquine 250 mg once a week for 24 weeks.
Measure Participants	99	102	99
Prophylactic Failure	93 93.9%	90 88.2%	92 92.9%
Prophylactic Success (total)	6 6.1%	12 11.8%	7 7.1%
Prophylactic Success (known)	0 0%	6 5.9%	0 0%
Prophylactic Success (assumed)	6 6.1%	6 5.9%	7 7.1%

2. Secondary Outcome

Title	Protective Efficacy Based on Two Consecutive Positive Smears
Description	Kaplan-Meier survival curves were produced for time to parasitaemia for both first positive smear and two consecutive positive smears. Analysis was based on a calculation of protective efficacy (PE) of tefaenoquine, defined as (1-relative risk of developing parasitaemia tafenoquine: placebo) x100% and 95.5% confidence intervals were constructed for the relative risk using Koopman's method.
Time Frame	24 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Tafenoquine	Mefloquine
Arm/Group Description	Placebo Placebo: Placebo for three days followed by placebo once a week for 24 weeks	Tafenoquine 200 mg for three days followed by Tafenoquine 200 once a week for 24 weeks. Tafenoquine: Tafenoquine 200 mg for three days followed by Tafenoquine 200 mg once a week for 24 weeks.	Mefloquine 250 mg for three days followed by Mefloquine 250 once a week for 24 weeks. Mefloquine: Mefloquine 250 mg for three days followed by Mefloquine 250 mg once a week for 24 weeks.
Measure Participants	99	102	99
Number (95% Confidence Interval) [Percentage of Protective Efficacy]	0	77.9	56.8

3. Secondary Outcome

Title	Time to a Single Positive Smear
Description	Kaplan-Meier survival curves were produced for time to parasitaemia for both first positive smear and two consecutive positive smears. 95.5% confidence intervals were constructed for the relative risk.
Time Frame	24 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Tafenoquine	Mefloquine
Arm/Group Description	Placebo Placebo: Placebo for three days followed by placebo once a week for 24 weeks	Tafenoquine 200 mg for three days followed by Tafenoquine 200 once a week for 24 weeks. Tafenoquine: Tafenoquine 200 mg for three days followed by Tafenoquine 200 mg once a week for 24 weeks.	Mefloquine 250 mg for three days followed by Mefloquine 250 once a week for 24 weeks. Mefloquine: Mefloquine 250 mg for three days followed by Mefloquine 250 mg once a week for 24 weeks.
Measure Participants	99	102	99
First positive smear	43	57	50
Two consecutive positve smears	63	0	165

4. Other Pre-specified Outcome

Title	Safety (SAEs and AEs)
Description	The most commonly reported experiences in subject occurring in at least 20% of subjects in any treatment group.
Time Frame	28 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Tafenoquine	Mefloquine
Arm/Group Description	Placebo Placebo: Placebo for three days followed by placebo once a week for 24 weeks	Tafenoquine 200 mg for three days followed by Tafenoquine 200 once a week for 24 weeks. Tafenoquine: Tafenoquine 200 mg for three days followed by Tafenoquine 200 mg once a week for 24 weeks.	Mefloquine 250 mg for three days followed by Mefloquine 250 once a week for 24 weeks. Mefloquine: Mefloquine 250 mg for three days followed by Mefloquine 250 mg once a week for 24 weeks.
Measure Participants	99	102	99
At least one AE	92 92.9%	98 96.1%	97 98%
Headache	37 37.4%	45 44.1%	49 49.5%
Upper Respiratory Tract Infection	17 17.2%	30 29.4%	26 26.3%
Back Pain	12 12.1%	28 27.5%	10 10.1%
Myalgia	25 25.3%	27 26.5%	29 29.3%
Abdominal Pain	24 24.2%	25 24.5%	19 19.2%
Coughing	13 13.1%	24 23.5%	29 29.3%
Rhinitis	21 21.2%	12 11.8%	20 20.2%

Adverse Events

Time Frame	28 weeks
Adverse Event Reporting Description	Subjects with the most frequently reported AEs (>10 % of subjects in any treatment group)
Arm/Group Title	Placebo		Tafenoquine		Mefloquine
Arm/Group Description	Placebo Placebo: Placebo for three days followed by placebo once a week for 24 weeks		Tafenoquine 200 mg for three days followed by Tafenoquine 200 once a week for 24 weeks. Tafenoquine: Tafenoquine 200 mg for three days followed by Tafenoquine 200 mg once a week for 24 weeks.		Mefloquine 250 mg for three days followed by Mefloquine 250 once a week for 24 weeks. Mefloquine: Mefloquine 250 mg for three days followed by Mefloquine 250 mg once a week for 24 weeks.
All Cause Mortality
	Placebo		Tafenoquine		Mefloquine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Tafenoquine		Mefloquine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/101 (4%)		10/104 (9.6%)		2/101 (2%)
Blood and lymphatic system disorders
Haemolytic Anaemia	0/101 (0%)	0	1/104 (1%)	1	0/101 (0%)	0
Gastrointestinal disorders
Enteritis	0/101 (0%)	0	1/104 (1%)	1	0/101 (0%)	0
Moniliasis GI	1/101 (1%)	1	0/104 (0%)	0	0/101 (0%)	0
Infections and infestations
Infection	1/101 (1%)	1	2/104 (1.9%)	2	0/101 (0%)	0
Cellulitis	0/101 (0%)	0	1/104 (1%)	1	0/101 (0%)	0
Pneumonia	1/101 (1%)	1	0/104 (0%)	0	0/101 (0%)	0
Pneumonia	1/101 (1%)	1	1/104 (1%)	1	1/101 (1%)	1
Injury, poisoning and procedural complications
Injury	0/101 (0%)	0	1/104 (1%)	1	0/101 (0%)	0
Nervous system disorders
Headache	0/101 (0%)	0	1/104 (1%)	1	0/101 (0%)	0
Psychiatric disorders
Anxiety	0/101 (0%)	0	0/104 (0%)	0	1/101 (1%)	1
Reproductive system and breast disorders
Unintended pregnancy	0/101 (0%)	0	1/104 (1%)	1	0/101 (0%)	0
Unintended pregnancy	0/101 (0%)	0	1/104 (1%)	1	0/101 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pharyngitis	1/101 (1%)	1	0/104 (0%)	0	0/101 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Tafenoquine		Mefloquine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	92/101 (91.1%)		98/104 (94.2%)		97/101 (96%)
Gastrointestinal disorders
Abdominal pain	24/101 (23.8%)	24	25/104 (24%)	25	19/101 (18.8%)	19
Gastroenteritis	9/101 (8.9%)	9	13/104 (12.5%)	13	14/101 (13.9%)	14
Infections and infestations
Infection	20/101 (19.8%)	20	19/104 (18.3%)	19	14/101 (13.9%)	14
Conjunctivitis	13/101 (12.9%)	13	12/104 (11.5%)	12	7/101 (6.9%)	7
Viral infection	7/101 (6.9%)	7	5/104 (4.8%)	5	11/101 (10.9%)	11
Injury, poisoning and procedural complications
Injury	8/101 (7.9%)	8	18/104 (17.3%)	18	14/101 (13.9%)	14
Musculoskeletal and connective tissue disorders
Back pain	12/101 (11.9%)	12	28/104 (26.9%)	28	10/101 (9.9%)	10
Myalgia	25/101 (24.8%)	25	27/104 (26%)	27	29/101 (28.7%)	29
Arthralgia	8/101 (7.9%)	8	12/104 (11.5%)	12	10/101 (9.9%)	10
Nervous system disorders
Headache	37/101 (36.6%)	37	45/104 (43.3%)	45	49/101 (48.5%)	49
Dizziness	7/101 (6.9%)	7	12/104 (11.5%)	12	14/101 (13.9%)	14
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract infection	17/101 (16.8%)	17	30/104 (28.8%)	30	26/101 (25.7%)	26
Coughing	13/101 (12.9%)	13	24/104 (23.1%)	24	29/101 (28.7%)	29
Pharyngitis	12/101 (11.9%)	12	14/104 (13.5%)	14	14/101 (13.9%)	14
Rhinitis	21/101 (20.8%)	21	12/104 (11.5%)	12	20/101 (19.8%)	20
Skin and subcutaneous tissue disorders
Pruritus	13/101 (12.9%)	13	13/104 (12.5%)	13	11/101 (10.9%)	11

Limitations/Caveats

Due to high failure rate a DMC was setup to assess if it was appropriate to continue study. DMC concluded that the study should continue in order to meet secondary objectives of evaluating the long-term safety and efficacy.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.