Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as Formulation A (ALS-008176), Formulation A, Treatment A, Treatment A (adult formulation), Treatment A (reference)
A/ B · 12 trials · 5 indications
Taste will be assessed using a questionnaire designed for the purpose. The questionnaire will consist of a visual analogue scale to rate 5 items (sweetness, bitterness, aroma type, aroma strength, and smell) as well as overall acceptability.
Pharmacokinetic profile will be determined by the following parameters: Cmax (Maximum plasma concentration), tmax (Time to reach Cmax), t1/2 (Terminal half-life), AUC(0-t) (Area under the plasma concentration-time curve from zero to time t of the last measured concentration above the limit of quantification), AUC(0-inf) (Area under the plasma concentration-time curve from zero to infinity)
The Cmax is the maximum observed plasma concentration of SMV.
The Tmax is the time to reach the maximum observed plasma concentration of SMV.
AUC (0-last) from time 0 to the time of the last measurable (non-below quantification limit \[BQL\]) concentration, calculated by linear-linear trapezoidal summation.
The AUC (0-infinity) is the area under the plasma concentration-time curve from time 0 to infinite time, calculated as the sum of AUC (0-last) and C(last)/lambda(z), in which AUC(0-last) is area under the plasma concentration-time curve from time zero to time of the last quantifiable concentration, C(last) is the last observed quantifiable concentration and lambda(z) is elimination rate constant.
The Lambda (z) determined by linear regression of the terminal points of the ln-linear plasma concentration-time curve.
The t(1/2) is defined as 0.693/Lambda (z).
Formulations will be assessed using Acceptability Questionnaire, which evaluates sweetness, bitterness, aroma type, aroma strength, smell and overall acceptability using visual analogue scales (VAS) with range from 0 (super bad) to 100 (super good).
Protocol-specified pharmacokinetic parameters will be determined from plasma samples collected after each administration of study drug to assess the relative bioavailability of TMC207.
Total number of days of diarrhea defined as 3 or more loose stools within a 24-hour period (WHO criteria) that meet the criteria of Bristol Stool Score 6-7.
| Arm | Type | Description |
|---|---|---|
| Session 1: Sequence 1 | EXPERIMENTAL | Participants will sequentially receive 5 milliliters (mL) of each 6 ALS-008176 formulations A B F C E D on day 1. |
| Session 1: Sequence 2 | EXPERIMENTAL | Participants will sequentially receive 5 mL of each 6 ALS-008176 formulations B C A D F E on day 1. |
| Session 1: Sequence 3 | EXPERIMENTAL | Participants will sequentially receive 5 mL of each 6 ALS-008176 formulations C D B E A F on day 1. |
| Session 1: Sequence 4 | EXPERIMENTAL | Participants will sequentially receive 5 mL of each 6 ALS-008176 formulations D E C F B A on day 1. |
| Session 1: Sequence 5 | EXPERIMENTAL | Participants will sequentially receive 5 mL of each 6 ALS-008176 formulations E F D A C B on day 1. |
| Session 1: Sequence 6 | EXPERIMENTAL | Participants will sequentially receive 5 mL of each 6 ALS-008176 formulations F A E B D C on day 1. |
| Session 2: Sequence 1 | EXPERIMENTAL | Participants will receive 5 mL of two best scoring formulations from Session 1 with 3 varying concentrations of sucralose (G1 G2 H3 G3 H2 H1). |
| Session 2: Sequence 2 | EXPERIMENTAL | Participants will receive 5 mL of two best scoring formulations from Session 1 with 3 varying concentrations of sucralose (G2 G3 G1 H1 H3 H2). |
| Session 2: Sequence 3 | EXPERIMENTAL | Participants will receive 5 mL of two best scoring formulations from Session 1 with 3 varying concentrations of sucralose (G3 H1 G2 H2 G1 H3). |
| Session 2: Sequence 4 | EXPERIMENTAL | Participants will receive 5 mL of two best scoring formulations from Session 1 with 3 varying concentrations of sucralose (H1 H2 G3 H3 G2 G1). |
| Session 2: Sequence 5 | EXPERIMENTAL | Participants will receive 5 mL of two best scoring formulations from Session 1 with 3 varying concentrations of sucralose (H2 H3 H1 G1 G3 G2). |
| Session 2: Sequence 6 | EXPERIMENTAL | Participants will receive 5 mL of two best scoring formulations from Session 1 with 3 varying concentrations of sucralose (H3 G1 H2 G2 H1 G3). |
| Sequence AB | EXPERIMENTAL | Subjects receive treatment A in Period 1 followed by treatment B in Period 2 with a washout phase of 10 to 14 days between the two treatment periods |
| Sequence BA | EXPERIMENTAL | Subjects receive treatment B in Period 1 followed by treatment A in Period 2 with a washout phase of 10 to 14 days between the two treatment periods |
| Panel1: Sequence 1 (ABC) | EXPERIMENTAL | Participants will receive Treatment A (150 milligram (mg) simeprevir (SMV) capsule with water under fed conditions) in Period 1; followed by Treatment B (3\*50 mg capsules of SMV \[including 50 mini-tablets of 1 mg each\] with water under fed conditions) in Period 2; followed by Treatment C (3\*50 mg dispersible SMV tablets dispersed in water under fed conditions) in Period 3. A washout period of at least 7 days will be maintained between each treatment period. |
| Panel1: Sequence 2 (BCA) | EXPERIMENTAL | Participants will receive Treatment B in Period 1; followed by Treatment C in Period 2; followed by Treatment A in Period 3. A washout period of at least 7 days will be maintained between each treatment period. |
| Panel1: Sequence 3 (CAB) | EXPERIMENTAL | Participants will receive Treatment C in Period 1; followed by Treatment A in Period 2; followed by Treatment B in Period 3. A washout period of at least 7 days will be maintained between each treatment period. |
| Panel1: Sequence 4 (CBA) | EXPERIMENTAL | Participants will receive Treatment C in Period 1; followed by Treatment B in Period 2; followed by Treatment A in Period 3. A washout period of at least 7 days will be maintained between each treatment period. |
| Panel1: Sequence 5 (BAC) | EXPERIMENTAL | Participants will receive Treatment B in Period 1; followed by Treatment A in Period 2; followed by Treatment C in Period 3. A washout period of at least 7 days will be maintained between each treatment period. |
| Panel1: Sequence 6 (ACB) | EXPERIMENTAL | Participants will receive Treatment A in Period 1; followed by Treatment C in Period 2; followed by Treatment B in Period 3. A washout period of at least 7 days will be maintained between each treatment period. |
| Panel 2: Sequence 1 (DEF) | EXPERIMENTAL | Participants will receive Treatment D (3\*50 mg SMV capsules \[including 50 mini-tablets of 1 mg each\] with water or 3\*50 mg dispersible SMV tablets dispersed in water under fed conditions) in Period 1; followed by Treatment E (3\*50 mg SMV capsules \[including 50 mini-tablets of 1 mg each\] with water or 3\*50 mg dispersible SMV tablets dispersed in water under fasted conditions) in Period 2; followed by Treatment F (3\*50 mg SMV capsules \[including 50 mini-tablets of 1 mg each\] with yoghurt or 3\*50 mg dispersible SMV tablets dispersed in apple juice under fed conditions) in Period 3. A washout period of at least 7 days will be maintained between each treatment period. |
| Panel 2: Sequence 2 (EFD) | EXPERIMENTAL | Participants will receive Treatment E in Period 1; followed by Treatment F in Period 2; followed by Treatment D in Period 3. A washout period of at least 7 days will be maintained between each treatment period. |
| Panel 2: Sequence 3 (FDE) | EXPERIMENTAL | Participants will receive Treatment F in Period 1; followed by Treatment D in Period 2; followed by Treatment E in Period 3. A washout period of at least 7 days will be maintained between each treatment period. |
| Panel 2: Sequence 4 (FED) | EXPERIMENTAL | Participants will receive Treatment F in Period 1; followed by Treatment E in Period 2; followed by Treatment D in Period 3. A washout period of at least 7 days will be maintained between each treatment period. |
| Panel 2: Sequence 5 (EDF) | EXPERIMENTAL | Participants will receive Treatment E in Period 1; followed by Treatment D in Period 2; followed by Treatment F in Period 3. A washout period of at least 7 days will be maintained between each treatment period. |
| Panel 2: Sequence 6 (DFE) | EXPERIMENTAL | Participants will receive Treatment D in Period 1; followed by Treatment F in Period 2; followed by Treatment E in Period 3. A washout period of at least 7 days will be maintained between each treatment period. |
| Session 2: Sequence 7 | EXPERIMENTAL | Participants will receive two best scoring formulations from Session 1 with a varying concentration of sucralose (M1M2M3N1N2N3) sequentially in a random order, at a dosing interval of 1-2 hours. |
| Session 2: Sequence 8 | EXPERIMENTAL | Participants will receive two best scoring formulations from Session 1 with a varying concentration of sucralose (M1M2M3N1N2N3) sequentially in a random order, at a dosing interval of 1-2 hours. |
| Session 2: Sequence 9 | EXPERIMENTAL | Participants will receive two best scoring formulations from Session 1 with a varying concentration of sucralose (M1M2M3N1N2N3) sequentially in a random order, at a dosing interval of 1-2 hours. |
| Session 2: Sequence 10 | EXPERIMENTAL | Participants will receive two best scoring formulations from Session 1 with a varying concentration of sucralose (M1M2M3N1N2N3) sequentially in a random order, at a dosing interval of 1-2 hours. |
| Session 2: Sequence 11 | EXPERIMENTAL | Participants will receive two best scoring formulations from Session 1 with a varying concentration of sucralose (M1M2M3N1N2N3) sequentially in a random order, at a dosing interval of 1-2 hours. |
| Session 2: Sequence 12 | EXPERIMENTAL | Participants will receive two best scoring formulations from Session 1 with a varying concentration of sucralose (M1M2M3N1N2N3) sequentially in a random order, at a dosing interval of 1-2 hours. |
| Sequence 1: abiraterone acetate | EXPERIMENTAL | Treatment sequence 1 is defined as: AEBD |
| Sequence 2: abiraterone acetate | EXPERIMENTAL | Treatment sequence 2 is defined as: BACE |
| Sequence 3: abiraterone acetate | EXPERIMENTAL | Treatment sequence 3 is defined as: CBDA |
| Sequence 4: abiraterone acetate | EXPERIMENTAL | Treatment sequence 4 is defined as: EDAC |
| Sequence 5: abiraterone acetate | EXPERIMENTAL | Treatment sequence 5 is defined as: DECA |
| Sequence 6: abiraterone acetate | EXPERIMENTAL | Treatment sequence 6 is defined as: EADB |
| Sequence 7: abiraterone acetate | EXPERIMENTAL | Treatment sequence 7 is defined as: ABEC |
| Sequence 8: abiraterone acetate | EXPERIMENTAL | Treatment sequence 8 is defined as: BCAD |
| Treatment Sequence ABC | EXPERIMENTAL | Participants in Panel 1 will take the sequence of 3 treatments with a standardized breakfast, participants in Panel 2 will take the sequence of 3 treatments with yogurt, and participants in Panel 3 will take the sequence of 3 treatments after a 10-hour overnight fast (without food). Each treatment in each treatment sequence to be separated by 4 weeks. |
| Treatment Sequence ACB | EXPERIMENTAL | Participants in Panel 1 will take the sequence of 3 treatments with a standardized breakfast, participants in Panel 2 will take the sequence of 3 treatments with yogurt, and participants in Panel 3 will take the sequence of 3 treatments after a 10-hour overnight fast (without food). Each treatment in each treatment sequence to be separated by 4 weeks. |
| Treatment Sequence BAC | EXPERIMENTAL | Participants in Panel 1 will take the sequence of 3 treatments with a standardized breakfast, participants in Panel 2 will take the sequence of 3 treatments with yogurt, and participants in Panel 3 will take the sequence of 3 treatments after a 10-hour overnight fast (without food). Each treatment in each treatment sequence to be separated by 4 weeks. |
| Treatment Sequence BCA | EXPERIMENTAL | Participants in Panel 1 will take the sequence of 3 treatments with a standardized breakfast, participants in Panel 2 will take the sequence of 3 treatments with yogurt, and participants in Panel 3 will take the sequence of 3 treatments after a 10-hour overnight fast (without food). Each treatment in each treatment sequence to be separated by 4 weeks. |
| Treatment Sequence CBA | EXPERIMENTAL | Participants in Panel 1 will take the sequence of 3 treatments with a standardized breakfast, participants in Panel 2 will take the sequence of 3 treatments with yogurt, and participants in Panel 3 will take the sequence of 3 treatments after a 10-hour overnight fast (without food). Each treatment in each treatment sequence to be separated by 4 weeks. |
| Treatment Sequence CAB | EXPERIMENTAL | Participants in Panel 1 will take the sequence of 3 treatments with a standardized breakfast, participants in Panel 2 will take the sequence of 3 treatments with yogurt, and participants in Panel 3 will take the sequence of 3 treatments after a 10-hour overnight fast (without food). Each treatment in each treatment sequence to be separated by 4 weeks. |
| Treatment A | PLACEBO_COMPARATOR | Treatment A: Florastor® 500 mg twice per day from Day 1 to Day 16 of the treatment period, and Zavesca® 100 mg three times per day from Day 3 to Day 16. For Period 2, subjects will receive the alternate dosing regimen. |
| Treatment B | EXPERIMENTAL | Treatment B: Florastor® 500 mg twice per day from Day 1 to Day 16 of the treatment period, and Zavesca® 100 mg three times per day from Day 3 to Day 16. For Period 2, subjects will receive the alternate dosing regimen. |
| Sequence group ADBC | EXPERIMENTAL | Treatment A: domperidone 10 mg; Treatment B: domperidone 20 mg; Treatment C: placebo; Treatment D: moxifloxacin. |
| Sequence group BACD | EXPERIMENTAL | Treatment A: domperidone 10 mg; Treatment B: domperidone 20 mg; Treatment C: placebo; Treatment D: moxifloxacin. |
| Sequence group CBDA | EXPERIMENTAL | Treatment A: domperidone 10 mg; Treatment B: domperidone 20 mg; Treatment C: placebo; Treatment D: moxifloxacin. |
| Sequence group DCAB | EXPERIMENTAL | Treatment A: domperidone 10 mg; Treatment B: domperidone 20 mg; Treatment C: placebo; Treatment D: moxifloxacin. |
| Treatment Sequence AB | EXPERIMENTAL | - |
| Treatment Sequence BA | EXPERIMENTAL | - |
| Name | Type | Description |
|---|---|---|
| Formulation A (ALS-008176) | DRUG | Reference formulation, 60 mg/mL ALS-008176 oral suspension without sweetener/flavor. |
| Formulation B (ALS-008176) | DRUG | 60 mg/mL ALS-008176 oral suspension containing 12 mg/mL sucralose. |
| Formulation C (ALS-008176) | DRUG | 60 mg/mL ALS-008176 oral suspension containing 4 mg/mL sucralose and strawberry flavor. |
| Formulation D (ALS-008176) | DRUG | 60 mg/mL ALS-008176 oral suspension containing 4 mg/mL sucralose and masking flavor and strawberry flavor. |
| Formulation E (ALS-008176) | DRUG | 60 mg/mL ALS-008176 oral suspension containing 4 mg/mL sucralose and masking flavor and cream vanille flavor. |
| Formulation F (ALS-008176) | DRUG | 60 mg/mL ALS-008176 oral suspension containing 4 mg/mL sucralose and fantasy fruit flavor. |
| Formulation G1 (ALS-008176) | DRUG | 60 mg/mL ALS-008176 oral suspension with concentration 1 of sucralose (maximum 12 mg/mL) and best flavor 1 from session 1. |
| Formulation G2 (ALS-008176) | DRUG | 60 mg/mL ALS-008176 oral suspension with concentration 2 of sucralose (maximum 12 mg/mL) and best flavor 1 from session 1. |
| Formulation G3 (ALS-008176) | DRUG | 60 mg/mL ALS-008176 oral suspension with concentration 3 of sucralose (maximum 12 mg/mL) and best flavor 1 from session 1. |
| Formulation H1 (ALS-008176) | DRUG | 60 mg/mL ALS-008176 oral suspension with concentration 1 of sucralose (maximum 12 mg/mL) and best flavor 2 from session 1. |
| Formulation H2 (ALS-008176) | DRUG | 60 mg/mL ALS-008176 oral suspension with concentration 2 of sucralose (maximum 12 mg/mL) and best flavor 2 from session 1. |
| Formulation H3 (ALS-008176) | DRUG | 60 mg/mL ALS-008176 oral suspension with concentration 3 of sucralose (maximum 12 mg/mL) and best flavor 2 from session 1. |
| Treatment A (adult formulation) | DRUG | Single oral administration of one film-coated tablet containing 10 mg of macitentan as active substance and lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate type A, polysorbate as inactive ingredients.The film coat contains titanium dioxide, talc, xanthan gum, polyvinyl alcohol, and soy lecithin. |
| Treatment B (pediatric formulation) | DRUG | Single oral administration of two dispersible tablets, each containing 5 mg of macitentan as active ingredient and Mannitol delta polymorphic crystals, mannitol, isomalt, isomalt agglomerated, croscarmellose sodium, and magnesium stearate as inactive ingredients. |
| Treatment A | DRUG | 150 milligram (mg) SMV capsule with water under fed conditions. |
| Treatment B | DRUG | Treatment B (3\*50 mg capsules of SMV (including 50 mini-tablets of 1 mg each) with water under fed conditions. |
| Treatment C | DRUG | Treatment C (3\*50 mg dispersible SMV tablets dispersed in water under fed conditions). |
| Treatment D | DRUG | \*50 mg SMV capsules (including 50 mini-tablets of 1 mg each) with water or 3\*50 mg dispersible SMV tablets dispersed in water under fed conditions. |
| Treatment E | DRUG | 3\*50 mg SMV capsules (including 50 mini-tablets of 1 mg each) with water or 3\*50 mg dispersible SMV tablets dispersed in water under fasted conditions. |
| Treatment F | DRUG | 3\*50 mg SMV capsules (including 50 mini-tablets of 1 mg each) with yoghurt or 3\*50 mg dispersible SMV tablets dispersed in apple juice under fed conditions. |
| Formulation A | DRUG | Reference formulation, 10 milligram/milliliter (mg/mL)oral solution without sweetener/flavor. |
| Formulation B | DRUG | 10 mg/mL oral solution containing 2 mg/mL sucralose, masking flavor and orange flavor. |
| Formulation C | DRUG | 10 mg/mL oral solution containing 10 mg/mL sucralose. |
| Formulation D | DRUG | 10 mg/mL oral solution containing 2 mg/mL sucralose and raspberry flavor. |
| Formulation E | DRUG | 10 mg/mL oral solution containing 2 mg/mL sucralose and strawberry flavor. |
| Formulation F | DRUG | 10 mg/mL oral solution containing 2 mg/mL sucralose and orange flavor. |
| Formulation M1 | DRUG | Best scoring formulation from Session 1 with a varying concentration of sucralose (maximum 10 mg/mL). |
| Formulation M2 | DRUG | Best scoring formulation from Session 1 with a varying concentration of sucralose (maximum 10 mg/mL). |
| Formulation M3 | DRUG | Best scoring formulation from Session 1 with a varying concentration of sucralose (maximum 10 mg/mL). |
| Formulation N1 | DRUG | Second best scoring formulation from Session 1 with a varying concentration of sucralose (maximum 10 mg/mL). |
| Formulation N2 | DRUG | Second best scoring formulation from Session 1 with a varying concentration of sucralose (maximum 10 mg/mL). |
| Formulation N3 | DRUG | Second best scoring formulation from Session 1 with a varying concentration of sucralose (maximum 10 mg/mL). |
| Treatment A (reference) | DRUG | One tablet equivalent to a single 100-mg dose of TMC207 taken orally (by mouth) once. |
| Treatment A (domperidone 10 mg) | DRUG | 1 domperidone 10 mg capsule four times a day (q.i.d.) + 1 domperidone placebo capsule q.i.d. on Days 1 to 3 and a single dose on Day 4 (13 doses in total), and 1 moxifloxacin placebo capsule in the morning of Day 1. |
| Treatment B (domperidone 20 mg) | DRUG | 2 domperidone 10 mg capsules four times a day (q.i.d.) on Days 1 to 3 and a single dose on Day 4 (13 doses in total), and 1 moxifloxacin placebo capsule in the morning of Day 1. |
| Treatment C (placebo) | DRUG | 2 domperidone placebo capsules four times a day (q.i.d.) on Days 1 to 3 and a single dose on Day 4 (13 doses in total), and 1 moxifloxacin placebo capsule in the morning of Day 1. |
| Treatment D (moxifloxacin) | DRUG | 2 domperidone placebo capsules four times a day (q.i.d.) on Days 1 to 3 and a single dose on Day 4 (13 doses in total), and 1 moxifloxacin 400 mg capsule in the morning of Day 1. |
| A (CANA/MET IR FDC tablet - fasting state) / B (CANA/MET IR FDC tablet - fed state) | DRUG | Treatment A: Type = 1, unit = mg, number = 150/1000, form = tablet, route = oral use. One CANA/MET IR FDC tablet taken orally (by mouth) in a fasting state on Day 1 of Treatment Period 1 followed 10-14 days later by Treatment B: Type = 1, unit = mg, number = 150/1000, form = tablet, route = oral use. One CANA/MET IR FDC tablet taken orally in a fed state on Day 1 of Treatment Period 2. |
| B (CANA/MET IR FDC tablet - fed state) / A (CANA/MET IR FDC tablet - fasting state) | DRUG | Treatment B: Type = 1, unit = mg, number = 150/1000, form = tablet, route = oral use. One CANA/MET IR FDC tablet taken orally in a fed state on Day 1 of Treatment Period 1 followed 10-14 days later by Treatment B: Type = 1, unit = mg, number = 150/1000, form = tablet, route = oral use. One CANA/MET IR FDC tablet taken orally in a fasting state on Day 1 of Treatment Period 2. |
| A (canagliflozin and metformin IR individual tablets) / B (canagliflozin/metformin IR FDC tablets) | DRUG | Treatment A: Canagliflozin: Type = 1, unit = mg, number = 100, form = tablet, route = oral use + metformin IR: Type = 2, unit = mg, number = 1000, form = tablet, route = oral use. One canagliflozin tablet and 2 metformin IR tablets taken orally (by mouth) on Day 1 of Treatment Period 1 followed 10-15 days later by Treatment B (canagliflozin/metformin IR FDC): Type = 2, unit = mg, number = 50/1000, form = tablet, route = oral use. Two canagliflozin/metformin IR FDC tablets taken orally on Day 1 of Treatment Period 2 |
| B (canagliflozin/metformin IR FDC tablets / A (canagliflozin and metformin IR individual tablets) | DRUG | Treatment B (canagliflozin/metformin IR FDC): Type = 2, unit = mg, number = 50/1000, form = tablet, route = oral use. Two Canagliflozin/metformin IR FDC tablets taken orally on Day 1 of Treatment Period 1 followed 10-15 days later by Treatment A: Canagliflozin: Type = 1, unit = mg, number = 100, form = tablet, route = oral use + Metformin IR: Type = 2, unit = mg, number = 1000, form = tablet, route = oral use. One canagliflozin tablet and 2 metformin IR tablets taken orally (by mouth) on Day 1 of Treatment Period 2. |
Inclusion Criteria: * Participant must be a man or woman between 18 and 65 years of age, inclusive, at Screening * Participant must sign an informed consent form (ICF) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the s...