Assessment of Any Potential Retinal Effects of Tafenoquine (TQ)

NCT02658435 | Completed Phase 1 DMC

• 1 other identifier: 201807
• Study Type: interventional
• Target: 486
• Locations: 1 country
• Sites: 3

Brief Summary

The study aims to provide evidence of retinal safety to support the use of tafenoquine as a potential single dose radical cure treatment for patients with Plasmodium vivax (P. vivax) malaria (i.e., co-administration of a schizonticidal drug with TQ). The study will be conducted as a single masked, randomized, placebo-controlled, parallel group design. It will assess retinal changes from baseline using spectral domain optical coherence tomography (OCT) and fundus auto fluorescence (FAF) at Month 3 (90 days) post-dose in adult healthy volunteers (participants). A placebo control group will be used to compare the results in the TQ group. Interim analysis will be conducted after completing 100 out of 300 participants in TQ group and 50 out of 150 participants in matched placebo.

Conditions

Malaria, Vivax

Keywords

Malaria; Retinal; Ophthalmic; Plasmodium. vivax; Tafenoquine; Pharmacodynamic

Outcome Measures

Primary Outcomes (4)

• Proportion of participants in the TQ group having retinal changes from Baseline in Central subfield thickness and Central retinal lesion thickness

  The change from baseline will be assessed as a binomial output as, Yes or No. Spectral domain OCT (SD-OCT) images/scan will be obtained. For Central subfield thickness and Central retinal lesion thickness, change from baseline of at least 40 microns (µ) will be consider 'Yes'. Central Retinal Lesion Thickness is defined as the distance between the inner limiting membrane of the retina and the inner border of the choriocapillaris measured in the central 1millimeter (mm) of the centre scan

  Baseline and Day 90(follow-up)

• Proportion of participants in the TQ group having retinal changes from Baseline in Total macular volume

  The change from baseline will be assessed as a binomial output as, Yes or No. SD-OCT images/scan will be obtained. Total Macular Volume, change from baseline of 10% will be considered 'Yes'

  Baseline and Day 90(follow-up)

• Proportion of participants in the TQ group having retinal changes from Baseline in Ellipsoid zone disruption

  The change from baseline will be assessed as a binomial output as, Yes or No. SD-OCT images/scan will be obtained. Ellipsoid zone disruption will be assessed by manual reading

  Baseline and Day 90(follow-up)

• Proportion of participants in the TQ group having retinal changes from Baseline in abnormal auto-fluorescence patterns

  The change from baseline will be assessed as a binomial output as, Yes or No. SD-OCT images/scan will be obtained. Abnormal auto-fluorescence will be assessed by FAF by manual reading

  Baseline and Day 90(follow-up)

Secondary Outcomes (10)

• Mean change from baseline in OCT parameter like central retinal thickness as a safety measure

  Baseline and Day 90(follow-up)

• Mean change from baseline in OCT parameter like central subfield thickness as a safety measure.

  Baseline and Day 90(follow-up)

• Mean change from baseline in OCT parameter like central retinal lesion thickness as a safety measure.

  Baseline and Day 90(follow-up)

• Mean change from baseline in OCT parameters;. Total macular volume as a safety measure.

  Baseline and Day 90(follow-up)

• Mean change from baseline in OCT parameters ;. Ellipsoid zone disruption as a safety measure.

  Baseline and Day 90(follow-up)

Study Arms (2)

Tafenoquine 300 milligram (mg) single dose

EXPERIMENTAL

Participants will receive single dose of TQ (2 tablets of 150mg) after standard meal. Participant will be randomized in a 2:1 ratio to 300mg TQ (n=300) or matched-placebo (n=150).

Drug: Tafenoquine 150 mg

Matched Placebo 300mg single dose

PLACEBO COMPARATOR

Participants will receive single dose of matched placebo (2 tablets of 150mg) after standard meal. Participant will be randomized in a 2:1 ratio to 300mg TQ (n=300) or matched-placebo (n=150).

Drug: Matched placebo 150mg

Interventions

Tafenoquine 150 mg DRUG

Tablet contains TQ as tafenoquine succinate. The 2 tablets (2 tablets of 150mg) of dark pink, capsule-shaped, film coated will be administered orally with 240ml of water.

Tafenoquine 300 milligram (mg) single dose

Matched placebo 150mg DRUG

It is the matched Placebo tablet. The 2 tablets (2 tablets of 150mg) of dark pink, capsule-shaped, film coated will be administered orally with 240ml of water.

Matched Placebo 300mg single dose

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Between 18 and 45 years of age inclusive, at the time of signing the informed consent.
• Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, brief physical examination, and laboratory tests.

You may not qualify if:

• Body weight between \>=35 kilogram (kg) and =\<100kg
• Male OR Female. Female participant is eligible to participate if she is not pregnant (as confirmed by a negative \[serum or urine, according to site standard\] human chorionic gonadotrophin \[hCG\] test), not lactating, and at least one of the following conditions applies:
• Non-reproductive potential defined as Pre-menopausal females with one of the following: Documented tubal ligation or Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion or Hysterectomy or Documented Bilateral Oophorectomy or Postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to site specific laboratory reference ranges for confirmatory levels). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.
• Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from screening until completion of the Day 90 follow-up visit.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
• Alanine Aminotransferase (ALT) and bilirubin \>1.5 times Upper Limit of Normal (ULN) (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• The QT interval corrected (QTc) for heart rate according to Fridericia's formula (QTcF). QTcF \> 450 milli second (msec). Other calculation methods (e.g. QT interval corrected for heart rate according to Bazett's formula \[QTcB\], individually corrected QT interval \[QTcI\]) machine-read or manually over-read are not acceptable.
• Use of prescription (except female contraception and acetaminophen at doses of =\<2 grams(g)/day) or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise participant safety.
• History of regular alcohol consumption within 30 days of the study defined as: an average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 millilitre \[mL\]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
• Positive results for drugs of abuse
• Cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 30 days prior to screening.
• History of sensitivity to TQ, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
• History of thalassaemia; or current or past history of methemoglobinemia or methemoglobin percentage above the reference range at screening.
• Lactating females.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Medicines for Malaria Venture: collaborator

Study Sites (3)

GSK Investigational Site

Glendale, California, 91206, United States

Location

GSK Investigational Site

Overland Park, Kansas, 66211, United States

Location

GSK Investigational Site

Baltimore, Maryland, 21225, United States

Location

Related Publications (1)

• Ackert J, Mohamed K, Slakter JS, El-Harazi S, Berni A, Gevorkyan H, Hardaker E, Hussaini A, Jones SW, Koh GCKW, Patel J, Rasmussen S, Kelly DS, Baranano DE, Thompson JT, Warren KA, Sergott RC, Tonkyn J, Wolstenholme A, Coleman H, Yuan A, Duparc S, Green JA. Randomized Placebo-Controlled Trial Evaluating the Ophthalmic Safety of Single-Dose Tafenoquine in Healthy Volunteers. Drug Saf. 2019 Sep;42(9):1103-1114. doi: 10.1007/s40264-019-00839-w.

  PMID: 31187437 DERIVED

MeSH Terms

Conditions

Malaria, Vivax; Malaria

Interventions

tafenoquine

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 4, 2016
• First Posted: January 18, 2016
• Study Start: February 2, 2016
• Primary Completion: September 14, 2017
• Study Completion: September 14, 2017
• Last Updated: March 1, 2018

Record last verified: 2018-02

Locations

US (3)