HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
LIMITATIONS OF THIS SNAPSHOT
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.
Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the FEXINIDAZOLE Prescribing Information for all of the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).
Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).
Sanofi Aventis US LLC
Approval date: July 16, 2021
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
FEXINIDAZOLE is a drug used to treat children 6 years of age and older who weigh at least 20 kg and adults who have an infection caused by Trypanosoma brucei gambiense.
Trypanosoma brucei gambiense infection (also called human African trypanosomiasis [g-HAT] or sleeping sickness is caused by a single-celled parasite transmitted by tsetse flies. The disease occurs in West and Central Africa. It can present in two stages. In the first stage (hemolymphatic) the patient may be without symptoms or have intermittent fevers, headaches, joint pain, itching and swelling of the lymph nodes. After 1 to 2 years, the infection spreads to the central nervous system leading to the second stage (meningoencephalitic), where the patient can have personality changes, confusion, daytime sleepiness, and coma.
FEXINIDAZOLE is indicated for treatment of both stages of disease, but for the second stage FEXINIDZOLE should only be used in patients if there are no other available treatment options.
How is this drug used?
FEXINIDAZOLE is available as a tablet to be taken by mouth with food once a day. The number of tablets will depend on the weight of the patient, the initial (loading) dose, or maintenance dose. The total duration of treatment is 10 days.
Who participated in the clinical trials?
The FDA approved FEXINIDAZOLE based on evidence from three clinical trials of 749 patients with infection caused by Trypanosoma brucei gambiense. The trials were conducted at 10 sites in the Democratic Republic of the Congo and the Central African Republic. All three trials provided evidence of both safety and efficacy.
What are the benefits of this drug?
FEXINIDAZOLE can clear the parasite that causes African trypanosomiasis from body fluids.
What are the benefits of this drug (results of trials used to assess efficacy)?
The efficacy of FEXINIDAZOLE as compared to nifurtimox-eflornithine combination therapy (NECT) in a controlled trial (Trial 1) in adults with late second stage g-HAT is summarized in Table 1 below.
Success rates at 18 months are shown for the modified intention-to-treat (mITT) population, which consisted of all randomized patients who received at least one dose of study treatment but excluded 5 randomized patients due to geopolitical unrest. The success rate in the FEXINIDAZOLE treatment arm was lower than in the NECT arm. Additionally, more deaths occurred in the FEXINIDAZOLE treatment arm at 24 months (n=9, 3.4%) compared to the NECT treatment arm (n=2, 1.6%). This decreased efficacy and increased mortality was noted in the subgroup of patients who had a cerebrospinal fluid (CSF) white blood cell count (WBC) >100 cells/µL at baseline. The results at 24 months were consistent with the results at 18 months with 24-month success rates of 89.7% (235/262) in the FEXINIDAZOLE treatment arm and 97.6% (124/127) in the NECT arm.
Table 1. Success Rates at 18 Months (mITT Population) in Trial 1
|Difference (97% CI*)|
|Success at 18 months†||239 (91.2%)||124 (97.6%)||-6.4% (-11.6%, -0.1%)|
|Success at 18 months by baseline CSF-WBC‡|
|Baseline CSF-WBC ≤100 cells/µL||100/102 (98.0%)||47/49 (95.9%)|
|Baseline CSF-WBC >100 cells/µL||139/160 (86.9%)||77/78 (98.7%)|
Source: Adapted from FDA Review
* Analysis adjusted for interim analysis to control the overall Type I error at two-sided 0.05.
† Two FEXINIDAZOLE treated patients were considered as failures due to loss to follow-up and consent withdrawal prior to 18 months.
‡ CSF-WBC represents white blood cell count in cerebrospinal fluid at baseline.
Abbreviations: CSF, cerebrospinal fluid; mITT, modified intent-to-treat; NECT, nifurtimox-eflornithine combination therapy; WBC, white blood cell
Additional supportive evidence for efficacy came from two single-arm trials, one in early-stage g-HAT in adults (Trial 2) and another in pediatric patients aged 6 to 15 years old and weighing at least 20 kg (Trial 3). In Trial 2, treatment success in all patients with first or late-stage g-HAT was 98.7% (227/230, 95% CI [96.2%, 99.7%]) at 12 months. In Trial 3, treatment success at 12 months was 97.6% (122/125, 95% CI [93.1%, 99.5%]). In both trials, the results at 18 months were consistent with the results at 12 months.
Were there any differences in how well the drug worked in clinical trials among sex, race and age?
- Sex: FEXINIDAZOLE worked similarly in males and females.
- Race: All clinical trials were conducted in Africa. No further information on race was available to allow an evaluation by race.
- Age: Very few patients above 65 years of age were studied. In Trial 1, FEXINIDAZOLE appeared to work better in patients above 45 years of age although this may have been due to less severe disease in this age group. In Trial 2, the treatment effect was similar across different age groups.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
Table 2. Subgroup Analysis of the Primary Efficacy Endpoint (Success Proportion at 18 Months) in the ITT Population in Trial 1
|Male||145/161 (90.1%)||76/80 (95.0%)|
|Female||94/103 (91.3%)||48/50 (98.0%)|
|<45||184/205 (89.8%)||92/96 (95.8%)|
|≥45||55/59 (93.2%)||32/34 (94.1%)|
|Age and CSF-WBC*|
|Age <45, WBC ≤100||62/65 (95.4%)||31/32 (96.9%)|
|Age <45, WBC >100||122/140 (87.1%)||61/64 (95.3%)|
|Age ≥45, WBC ≤100||38/38 (100%)||16/18 (88.9%)|
|Age ≥45, WBC >100||17/21 (81.0%)||16/16 (100%)|
Source: Adapted from FDA Review
* CSF-WBC represents white blood cell count in cerebrospinal fluid at baseline.
Abbreviations: CSF, cerebrospinal fluid; ITT, intent-to-treat; NECT, nifurtimox-eflornithine combination therapy; WBC, white blood cell
Table 3. Subgroup Analysis of the Primary Efficacy Endpoint (Success Proportion at 12 Months) in the ITT Population in Trials 2 and 3
|Male||112/115 (97.4%)||66/67 (98.5%)|
|Female||115/115 (100%)||56/58 (96.6%)|
|<45||160/162 (98.8%)||122/125 (97.5%)|
|≥45||67/68 (98.5%)||Not available|
Source: Adapted from FDA Review
Abbreviations: ITT, intent-to-treat
What are the possible side effects?
The most common side effects are headache, vomiting, difficulty sleeping, and nausea. Serious side effects include disturbance in the heart electrical system (QT prolongation), neuropsychiatric problems such as anxiousness, personality changes, or hallucination, reduced counts of blood cells that fight infection (neutropenia), and liver abnormalities. Patients should avoid drinking alcohol while on FEXINIDAZOLE.
What are the possible side effects (results of trials used to assess safety)?
Table 4. Common Side Effects Occurring in ≥10% of HAT Patients 15 Years of Age and Older Receiving Fexinidazole Tablets in Trial 1
|Headache||92 (34.8)||32 (24.6)|
|Vomiting||75 (28.4)||37 (28.5)|
|Insomnia||74 (28.0)||15 (11.5)|
|Nausea||68 (25.8)||26 (20.0)|
|Asthenia||60 (22.7)||19 (14.6)|
|Tremor||58 (22.0)||15 (11.5)|
|Decreased appetite||56 (21.2)||24 (18.5)|
|Dizziness||50 (18.9)||18 (13.8)|
|Hypocalcaemia||36 (13.6)||3 (2.3)|
|Dyspepsia||34 (12.9)||10 (7.7)|
|Back pain||30 (11.4)||12 (9.2)|
|Abdominal pain upper||27 (10.2)||6 (4.6)|
|Hyperkalaemia||27 (10.2)||25 (19.2)|
Source: adae.xpt; Software: R
Coded as MedDRA preferred terms.
Abbreviations: N, number of patients in treatment arm; n, number of patients with side effect
Were there any differences in side effects among sex, race and age?
- Sex: The overall occurrence of side effects in Trial 1 was similar in males and females. Vomiting appeared to occur more in females than males (36% vs. 24%, respectively), and insomnia occurred more in males than females (32% vs. 22%, respectively).
- Race: All clinical trials were conducted in Africa. No information on race was available to allow an evaluation by race.
- Age: The side effect profile was generally similar in adult and pediatric patients in Trials 2 and 3 though vomiting appeared to occur with a higher incidence in children.
Were there any differences in side effects of the clinical trials among sex, race, and age groups?
Table 1. Overview of Side Effects by Sex and Age in Trial 1, Safety Population
|Grades 3 to 5
|Grades 3 to 5
|Sex, n (%)|
|Female||103 (39.0)||97/103 (94.2)||22/103 (21.4)||50 (38.5)||47/50 (94.0)||10/50 (20.0)|
|Male||161 (61.0)||150/161 (93.2)||38/161 (23.6)||80 (61.5)||74/80 (92.5)||18/80 (22.5)|
|Age group, n (%)|
|≤15 years||6 (2.3)||6/6 (100)||1/6 (16.7)||3 (2.3)||3/3 (100)||1/3 (33.3)|
|>15 to <45 years||198 (75.0)||181/198 (91.4)||32/198 (16.2)||93 (71.5)||88/93 (94.6)||21/93 (22.6)|
|≥45 years||60 (22.7)||60/60 (100)||27/60 (45.0)||34 (26.2)||30/34 (88.2)||6/34 (17.6)|
Source: FDA reviewer’s analysis
Abbreviation: N, number of patients in the safety population; n, number of patients with given characteristic; Ns, total number of patients in each category
Figure 1 summarizes how many men and women were enrolled in the combined clinical trials used to evaluate the efficacy of FEXINIDAZOLE.
Figure 1. Baseline Demographics by Sex in the Intent-to-Treat Population for Trials 1, 2, and 3
Source: Adapted from FDA Review
Demographics of Efficacy Trials by Race
As the trials were conducted in Africa, no race information was available and no analysis by race was performed.
Demographics of Efficacy Trials by Age
Very few patients ≥65 years old were enrolled into the clinical trials (7 such patients were enrolled in Trial 1).
How were the trials designed?
FEXINIDAZOLE was evaluated in 3 clinical trials of 749 patients with an infection caused by Trypanosoma brucei gambiense. These three trials included all stages of g-HAT and patients aged between 6 and 73 years old.
The three trials included one open-label, active-controlled trial with NECT as the active control and two single-arm, open-label trials.
Trial 1 was conducted in 394 patients aged 15 years or older with late Stage 2 g-HAT. The FEXINIDAZOLE tablet group received 1,800 mg of FEXINIDAZOLE tablets orally once daily on Days 1 through 4, followed by 1,200 mg orally once daily on Days 5 through 10, with all dosing in the fed state. The primary efficacy endpoint was treatment outcome at 18 months after end of the treatment. The outcome at 18 months was considered a success if patients were classified as a cure or probable cure as defined below:
- Cure: Patient is alive with no evidence of trypanosomes in any body fluid and CSF-WBC ≤20 cells/µL.
- Probable cure for patients who refused a lumbar puncture (or who had a hemorrhagic CSF sample) at 18 months: No parasites in the blood or lymph and a satisfactory clinical condition without clinical signs or symptoms (or clinical status is unlikely to be due to g HAT), CSF-WBC <50 cells/µL at 6 and/or 12 months and not increasing at 12 months, as long as there was no indication of a relapse up to 24 months and no definitive failure (presence of trypanosomes) had been observed before in any body fluid.
Trial 2 was conducted in Stage 1 (cerebral spinal fluid white blood cell count [CSF-WBC] ≤5 cells/μL) and early Stage 2 (CSF-WBC 6 to 20 cells/μL) g-HAT patients aged 15 years or older (n=230). FEXINIDAZOLE tablets 1,200 mg, was given in fed condition once a day on Days 1 through 4, followed by 600 mg on Days 5 through 10 to patients weighing <35 kg, and all other patients received the adult dosing regimen.
Trial 3 was conducted in Stage 1, and early and late Stage 2 g-HAT children at least 6 years old and <15 years and weighing over 20 kg (n=125). Doses were the same as in Trial 2.
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.