Malaria: Relative Bioavailability and Food Effect of DSM265

Study Overview
=================
Brief Summary
-----------------
Phase 1 study designed to evaluate the relative bioavailability of a single dose of a test formulation, DSM265-TPGS 34% SDD powder in comparison with a reference DSM265 25% SDD powder formulation used in early clinical trials.

Detailed Description
-----------------
The objective of this study is to compare the relative bioavailability of oral DSM265-TPGS 34% SDD formulation with that of a reference 25% SDD powder for suspension used in previous clinical trials. Another objective of the study is to evaluate the effect of food on bioavailability of the DSM265-TPGS 34% SDD formulation. The current 25% SDD powder for suspension clinical formulation is a suspension which requires reconstitution/administration in 240 mL sucralose based vehicle (for a 400 mg adult dose). This volume is too large for paediatric patients with malaria (e.g., translates into a 30 mL volume for 0.5-2 yr old patients); also, the dosing vehicle is not commercially viable. The new formulation dissolves in a smaller volume of a more common vehicle, water (40 mL for 400 mg adult dose).

Official Title
-----------------
Relative Bioavailability and Effect of Food on DSM265-TPGS 34% SDD Powder in Healthy Adult Subjects

Conditions
-----------------
Healthy Volunteers

Intervention / Treatment
-----------------
* Drug: DSM265-TPGS 34% SDD, 400 mg fasted
* Drug: DSM265-TPGS 34% SDD, 400 mg fed
* Drug: DSM265 25% SDD, 400 mg fasted


Participation Criteria
=================
Eligibility Criteria
-----------------
Subjects or their legally authorized representative must voluntarily sign and date each informed consent, approved by an Independent Ethics Committee(IEC) / Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures. Male or female between 18 and 55 years of age inclusive at the time of screening. Body Mass Index (BMI) is ≥ 18.0 to ≤ 29.9 kg/m2 after rounding to the tenths decimal. BMI is calculated as weight in kg divided by the square of height measured in meters. Females must be of Non-Childbearing Potential as defined below Females do not need to use birth control during or following study drug treatment if considered of non-childbearing potential due to meeting any of the following criteria: Postmenopausal, age ≤ 55 years with no menses for 12 or more months without an alternative medical cause AND an follicle stimulating hormone (FSH) level > 40 IU/L. Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy). Female who is not pregnant, breastfeeding, or considering becoming pregnant during the study or for approximately 120 days after the last dose of study drug. Male subjects who are sexually active with a female partner of childbearing potential, must agree to use condoms, even if the male subject has undergone a successful vasectomy, from Study Day 1 through 120 days after the last dose of study drug. His female partner(s) must also use at least one of the following methods of birth control: Combined (oestrogen and progestogen containing) hormonal birth control (oral, intravaginal, injectable, transdermal) associated with inhibition of ovulation initiated at least 30 days prior to study Baseline Day 1. Progestogen-only hormonal birth control (oral, injectable, implantable) associated with inhibition of ovulation initiated at least 30 days prior to study Baseline Day 1. Bilateral tubal occlusion/ligation. Intrauterine device (IUD). Intrauterine hormone-releasing system (IUS). Male who is not considering fathering a child or donating sperm during the study or for approximately 120 days after the last dose of study drug. Laboratory values meet the following criteria: Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ the upper limit of normal (ULN) at the Screening Visit and upon initial confinement. Negative test result for hepatitis A virus immunoglobulin M (HAV-IgM), hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody (Ab) and human immunodeficiency virus (HIV) at screening visit. Negative screen for drugs of abuse, alcohol or cotinine at screening and upon initial confinement. For non-postmenopausal female subjects, a negative urine pregnancy test at the screening visit and a negative serum pregnancy test upon initial confinement and prior to the first dose of study drug. No other laboratory results that the investigator determines are clinically significant. Platelets greater than or equal to the lower limit of normal. No clinically significant ECG abnormalities including No evidence of 2nd or 3rd degree AV block at screening visit and upon initial confinement. QT interval corrected for heart rate (QTc) using Fridericia's correction formula (QTcF) is ≤ 430 msec (males) or ≤ 450 msec (females) at screening visit and upon initial confinement. A condition of general good health, based upon the results of a medical history, physical examination, vital signs, laboratory profile and a 12-lead ECG. No history of: epilepsy, any clinically significant cardiac, respiratory (except mild asthma as a child), renal, hepatic, gastrointestinal, hematologic or psychiatric disease or disorder, or any uncontrolled medical illness. No history of any clinically significant sensitivity or allergy to any medication or food. No history of or active medical condition(s) or surgical procedure(s) that might affect gastrointestinal motility, pH, or absorption [e.g., Crohn's disease, celiac disease, gastroparesis, short bowel syndrome, gastric surgery (except pyloromyotomy for pyloric stenosis during infancy), cholecystectomy, vagotomy, bowel resection]. No evidence of dysplasia or history of malignancy (including lymphoma and leukemia) other than successfully treated non-metastatic cutaneous squamous cell, basal cell carcinoma or localized carcinoma in situ of the cervix. No history of any clinically significant illness/infection/major febrile illness, hospitalization, or any surgical procedure within 30 days prior to the first dose of study drug. Has not donated blood (including plasmapheresis), lost ≥ 550 mL blood volume, or received a transfusion of any blood product within 8 weeks prior to study drug administration. No consumption of alcohol, grapefruit products, Seville oranges, starfruit products or quinine/tonic water within the 72-hour period prior to study drug administration. No use of tobacco or nicotine-containing products within 180 days prior to the first dose of study drug. No history of clinically significant (per Investigator's judgment) drug or alcohol abuse within the last 6 months. Is not currently enrolled in another interventional clinical study. Has not been previously enrolled in this study. In the opinion of the investigator, this subject is a suitable candidate for enrollment in the study. Subjects must not have been treated with any investigational drug within 30 days or 5 half-lives of the drug (whichever is longer) prior to the first dose of study drug. Subject must not have received any live vaccine within 4 weeks prior to the first dose of study drug, or expected need of live vaccination during study participation including at least 4 weeks after the last dose of study drug. Subject must not require any over-the-counter and/or prescription medication, vitamins and/or herbal supplements, with the exception of contraceptives or hormonal replacement therapies for females, on a regular basis. Subject must not use any medications within the 2-week period prior to study drug administration. Receipt of any drug by injection within 30 days or within a period defined by 5 half-lives, whichever is longer, prior to study drug administration. No use of known inhibitors (e.g., ketoconazole) or inducers (e.g., carbamazepine) of cytochrome P450 3A (CYP3A) within 1 month prior to study drug administration. No exposure to DSM265 within the past 90 days prior to first dose of study drug.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 1, single-dose, open-label, randomized, parallel group design in healthy adults (males, females of non child bearing potential) in 3 groups of 14 subjects each.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DSM265-TPGS 34% SDD, 400 mg fasted<br>Spray dried dispersion (SDD) formulation, powder containing 34.25% DSM265-TPGS (tocopheryl polyethylene glycol succinate) | Drug: DSM265-TPGS 34% SDD, 400 mg fasted<br>* New formulation allowing smaller volumes of dissolution in a common vehicle (water), administered to subjects in a fasted state.<br>* Other names: DSM265;|
| Active Comparator: DSM265-TPGS 34% SDD, 400 mg fed<br>Spray dried dispersion (SDD) formulation, powder containing 34.25% DSM265-TPGS (tocopheryl polyethylene glycol succinate) | Drug: DSM265-TPGS 34% SDD, 400 mg fed<br>* New formulation allowing smaller volumes of dissolution in a common vehicle (water), administered to subjects in a fed state.<br>* Other names: DSM265;|
| Active Comparator: DSM265 25% SDD, 400 mg fasted<br>Spray dried dispersion (SDD) formulation, powder containing 25% DSM265 as free base | Drug: DSM265 25% SDD, 400 mg fasted<br>* Reference formulation used in early clinical trials.<br>* Other names: DSM265;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | Maximum observed DSM265 plasma concentration | 21 days | 
| AUC168 | Area under the plasma concentration-time curve from time 0 to 168 hours (AUC168) | 168 hours | 
| AUCt | AUC from time 0 until the last measurable concentration (AUCt), | 21 days | 
| Tmax | Time to Cmax. | 21 days | 
| β | Apparent terminal phase elimination rate constant | 21 days | 
| C168 | Plasma concentration at 168 hours | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUCinf | AUC from time 0 to infinity (AUCinf) | 21 days |