Epilepsy, Neurocysticercosis
Conditions
Keywords
neurocysticercosis, NCC, praziquantel, PZQ, albendazole, ABZ, parasite, pig tapeworm, Taenia solium, epilepsy, late-onset epilepsy, acquired epilepsy
Brief summary
The purpose of this study is to determine if combination drug therapy of praziquantel and albendazole is safe and effective to cure neurocysticercosis.
Detailed description
Neurocysticercosis is the single major cause of acquired or late-onset epilepsy in the world, and a common diagnosis in immigrant populations in the United States and other industrialized countries. An estimated 50 million humans are affected by Neurocysticercosis. The disease occurs when a parasite called Taenia solium, or the pig tapeworm, infects the brain, forming cysts. Neurocysticercosis is generally treated with 1 of 2 drugs, praziquantel or albendazole. However, current treatment with either of these drugs alone is not totally effective. The goal of this trial is to determine if combination drug therapy of praziquantel and albendazole is safe and more effective to cure Neurocysticercosis than either drug administered alone. This trial will consist of two sub-studies and a parent study. In the first substudy which was performed and completed as the initial part and guide to the design of the parent study, a series of 32 patients with viable cystic intraparenchymal Neurocysticercosis were treated with either albendazole ( 15 mg / kg /d ) + praziquantel ( 50 mg / kg/ d ) or albendazole+Placebo in a double blind randomized study. Half of patients in each group had their seizure disorder treated with phenytoin and the other half with carbamazepine (not assigned by the study). The study was designed and powered for pharmacokinetic evaluation and exploratory safety so comparative cysticidal efficacy has not yet been analyzed. There were no safety concerns. Pharmacokinetics of ABZ and PZQ were obtained and described. In the parent study, a total of 240 participants ( including the 32 participants from the first substudy ) will be randomly chosen to receive albendazole + praziquantel, albendazole + placebo or albendazole at an increased dose + placebo for 10 days. These groups will also receive other standard medications to manage the disease including appropriate anti-epileptic drug therapy. Participants will stay in the hospital for at least 2 weeks after treatment begins, which includes 5 days after the end of anti-parasitic treatment. After discharge from the hospital, follow-up visits will be on days 21 and 30 after treatment begins, then monthly until day 90, and finally every 3 months until completing 18 months. Brain images will be taken at 6 and 12 months after treatment begins. For participants, duration of the trial is 1 year and a half.
Interventions
DRUGPraziquantel
\- Praziquantel 50 mg / kg / d (up to 3600 mg / d ) for 10 days.
DRUGAlbendazole
* Albendazole 15 mg / kg / d ( up to 800 mg /d ) in Arm I for 10 days. * Albendazole at an increased dose, 22.5 mg / kg / d (up to 1200 mg / d ), in Arm II for 10 days.
DRUGABZ Placebo
\- Placebo (of Albendazole ) 7.5 mg / kg / d in Arm I and II for 10 days.
DRUGPZQ Placebo
\- Placebo (of Praziquantel) 50 mg / kg / d in Arm II and III for 10 days.
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Universidad Peruana Cayetano Heredia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
For parent study: Inclusion Criteria: * Male or female individuals between 16 to 65 years of age, with a diagnosis of Neurocysticercosis and 20 or less viable cysts. * Patients with a diagnosis of epilepsy secondary to Neurocysticercosis and a history of one or more spontaneous seizures within the previous year but not longer than 10 years. * Willingness to complete a minimum of two weeks of hospitalization. * If female of child bearing potential, negative urine pregnancy testing and willingness to use an adequate method of contraception while on study medications and for at least 3 months following Albendazole therapy. * Normal laboratory values for hematocrit, platelets, white blood cells and glucose and normal or decreased values for Alanine transaminase, Aspartate transaminase and creatinine. * Negative PPD measurement and if positive ( \> 9mm induration in the absence of other findings or immunosuppression ) , negative smears for TB. * Negative fecal exam for Taenia eggs or Strongyloides larvae.
Exclusion criteria
* Primary generalized seizures ( e.g., not caused by Neurocysticercosis ) * A history of generalized epileptic status . * A type of Neurocysticercosis which can expose the patient to increased risk during the study. * Patients with persistent or progressive symptomatic intracranial hypertension or intracranial hypertension. * Previous therapy with Albendazole or Praziquantel in the previous year. * Pulmonary tuberculosis, or symptoms compatible with tuberculosis not otherwise explained. * Active hepatitis * Systemic disease that may affect short term prognosis. * Patients in unstable condition ( consistently abnormal vital signs: body temperature, heart rate, respiratory rate, and blood pressure ) * Pregnancy during antiparasitic treatment * History of hypersensitivity to Albendazole or Praziquantel * Concurrent treatment with Cimetidine or Theophylline * Chronic alcohol or drug abuse * Unwilling or unable to provide a Computed tomography initially or an Magnetic resonance imaging at 6 months ( as patients with ferromagnetic implants ) , Computed tomography at the end of therapy. * Unwillingness of subject or legal representative to give written informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PK Substudy - Area Under the Curve of Albendazole in Treatment in Day 1 | 0, 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 12 hours post dose on Treatment day 1 | \- To evaluate kinetic disposition of Albendazole we calculated the Area under the curve of the active metabolite of Albendazole (Albendazole Sulphoxide) with Praziquantel or Placebo (of Praziquantel). |
| PK Substudy - Area Under the Curve of Albendazole in Treatment Days 10 and 11 | 0.5, 1, 1.5, 2, 3, 4, 8, 10, 12, 24 and 36 hours post dose on Treatment days 10-11 | \- To evaluate kinetic disposition of Albendazole we calculated the Area under the curve of the active metabolite of Albendazole (Albendazole Sulphoxide) with Praziquantel or Placebo (of Praziquantel). |
| PK Substudy - Maximum Concentration of Albendazole | Treatment day 1 and Treatment days 10-11 | Highest serum level of Albendazole measured from all level assessments in the curve. |
| Phase III Trial - Proportion of Patients Without Remaining Live Cysts | Day 180 | Proportion of patients whose 6 month MR does not show viable parasites anymore |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK Substudy - Area Under the Curve of Praziquantel by Antiepileptic Drug in Treatment Day 1 | 0, 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 12 hours post dose in treatment day 1 | \- To evaluate the kinetic disposition of Praziquantel by antiepileptic drug after the last praziquantel dose, we calculated the Area Under the Curve of Praziquantel with Carbamazepine or Phenytoin |
| Phase III Trial - Seizure Frequency | Day 1 - 540 | Seizure frequency by treatment group |
| PK Substudy - Area Under the Curve of Praziquantel by Antiepileptic Drug in Treatment Days 10 and 11 | 0.5, 1, 1.5, 2, 3, 4, 8, 10, 12, 24 and 36 hours post dose on treatment days 10-11 | \- To evaluate the kinetic disposition of Praziquantel by antiepileptic drug after the last praziquantel dose, we calculated the Area Under the Curve of Praziquantel with Carbamazepine or Phenytoin |
| PK Substudy - Safety of Combined Albendazole Plus Praziquantel Therapy | 90 days post tx | \- Describe if some Serious Adverse Event was associated to combined Albendazole plus Praziquantel therapy. |
| Phase III Trial - Proportion of Cysts Which Resolved | Day 180 | Proportion of Viable Brain Parasites which Are not Alive Anymore at 6 Months MRI |
Countries
Peru
Participant flow
Recruitment details
This protocol (2 groups, n=180) was modified by the DSMB to add a pharmacokinetics / safety substudy (two groups, n=32). After the substudy results were available, we were approved to proceed with a modified study design (3 groups, n=240). This second study was terminated after enroling patient 124 because of early efficacy (total n= 132+24, 156)
Participants by arm
| Arm | Count |
|---|---|
| Albendazole + Praziquantel * Albendazole was given at 15 mg / kg / d , divided two daily doses, morning and evening. It is supplied in 200 mg tablets, so the dose was rounded up to the next 100 mg level, up to a maximum 800 mg / d , for 10 days.
* Praziquantel was given at 50 mg / kg / d , divided in two daily doses, morning and evening.It is supplied in 600 mg tablets divided in four, so the dose was rounded up to the next 100 mg level, up to a maximum 3.6 g / d , for 9 1/2 days. | 16 |
| Albendazole + Placebo * Albendazole was given at 15 mg / kg / d , divided two daily doses, morning and evening. It is supplied in 200 mg tablets, so the dose was rounded up to the next 100 mg level, up to a maximum 800 mg / d , for 10 days.
* Praziquantel placebo was given in two daily doses, morning and evening,for 9 1/2 days. | 16 |
| Phase III Trial ABZ+PZQ * Albendazole was given at 15 mg / kg / d , divided two daily doses, morning and evening. It is supplied in 200 mg tablets, so the dose was rounded up to the next 100 mg level, up to a maximum 800 mg / d , for 10 days.
* A placebo of ABZ was added to complete to the doses in the Increased ABZ arm
* Praziquantel was given at 50 mg / kg / d , divided in two daily doses, morning and evening.It is supplied in 600 mg tablets divided in four, so the dose was rounded up to the next 100 mg level, up to a maximum 3.6 g / d , for 10 days. | 41 |
| Phase III Trial Increased ABZ * Albendazole was given at 22.5 mg / kg / d , divided in two daily doses, morning and evening. It is supplied in 200 mg tablets, so the dose was rounded up to the next 100 mg level, up to a maximum of 1200 mg / d , for 10 days.
* Praziquantel placebo was given in two daily doses, morning and evening,for 10 days. | 40 |
| Phase III Trial Standard ABZ * Albendazole was given at 15 mg / kg / d , divided two daily doses, morning and evening. It is supplied in 200 mg tablets, so the dose was rounded up to the next 100 mg level, up to a maximum 800 mg / d , for 10 days.
* A placebo of ABZ was added to complete the doses to the dosage in the Increased ABZ arm
* Praziquantel placebo was given in two daily doses, morning and evening,for 10 days. | 43 |
| Total | 156 |
Baseline characteristics
| Characteristic | Total | Albendazole + Praziquantel | Albendazole + Placebo | Phase III Trial Standard ABZ | Phase III Trial ABZ+PZQ | Phase III Trial Increased ABZ |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 8 Participants | 2 Participants | 2 Participants | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 146 Participants | 14 Participants | 14 Participants | 41 Participants | 39 Participants | 38 Participants |
| Age, Continuous | 28 years STANDARD_DEVIATION 10.2 | 29.3 years STANDARD_DEVIATION 9.7 | 27.5 years STANDARD_DEVIATION 11 | 35 years STANDARD_DEVIATION 13 | 34 years STANDARD_DEVIATION 14 | 34 years STANDARD_DEVIATION 12 |
| Region of Enrollment Peru | 156 participants | 16 participants | 16 participants | 43 participants | 41 participants | 40 participants |
| Sex: Female, Male Female | 59 Participants | 5 Participants | 6 Participants | 14 Participants | 15 Participants | 19 Participants |
| Sex: Female, Male Male | 97 Participants | 11 Participants | 10 Participants | 29 Participants | 26 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 16 | 12 / 16 |
| serious Total, serious adverse events | 2 / 16 | 2 / 16 |
Outcome results
Primary
Phase III Trial - Proportion of Patients Without Remaining Live Cysts
Proportion of patients whose 6 month MR does not show viable parasites anymore
Time frame: Day 180
Population: Some patients did not reach the analysis time point.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Albendazole + Praziquantel | Phase III Trial - Proportion of Patients Without Remaining Live Cysts | 25 participants |
| Albendazole + Placebo | Phase III Trial - Proportion of Patients Without Remaining Live Cysts | 19 participants |
| Phase III Trial - Standard ABZ | Phase III Trial - Proportion of Patients Without Remaining Live Cysts | 15 participants |
Primary
PK Substudy - Area Under the Curve of Albendazole in Treatment Days 10 and 11
\- To evaluate kinetic disposition of Albendazole we calculated the Area under the curve of the active metabolite of Albendazole (Albendazole Sulphoxide) with Praziquantel or Placebo (of Praziquantel).
Time frame: 0.5, 1, 1.5, 2, 3, 4, 8, 10, 12, 24 and 36 hours post dose on Treatment days 10-11
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Albendazole + Praziquantel | PK Substudy - Area Under the Curve of Albendazole in Treatment Days 10 and 11 | 4925.3 ng*h/ml |
| Albendazole + Placebo | PK Substudy - Area Under the Curve of Albendazole in Treatment Days 10 and 11 | 2969.6 ng*h/ml |
Primary
PK Substudy - Area Under the Curve of Albendazole in Treatment in Day 1
\- To evaluate kinetic disposition of Albendazole we calculated the Area under the curve of the active metabolite of Albendazole (Albendazole Sulphoxide) with Praziquantel or Placebo (of Praziquantel).
Time frame: 0, 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 12 hours post dose on Treatment day 1
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albendazole + Praziquantel | PK Substudy - Area Under the Curve of Albendazole in Treatment in Day 1 | 1412.2 ng*h/mL | 95% Confidence Interval 58124.7 |
| Albendazole + Placebo | PK Substudy - Area Under the Curve of Albendazole in Treatment in Day 1 | 1111 ng*h/mL | 95% Confidence Interval 32257.1 |
Primary
PK Substudy - Maximum Concentration of Albendazole
Highest serum level of Albendazole measured from all level assessments in the curve.
Time frame: Treatment day 1 and Treatment days 10-11
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albendazole + Praziquantel | PK Substudy - Maximum Concentration of Albendazole | 1293.9 ng/mL | Standard Deviation 3471.6 |
| Albendazole + Placebo | PK Substudy - Maximum Concentration of Albendazole | 2232.8 ng/mL | Standard Deviation 6500.7 |
Secondary
Phase III Trial - Proportion of Cysts Which Resolved
Proportion of Viable Brain Parasites which Are not Alive Anymore at 6 Months MRI
Time frame: Day 180
Population: Final population numbers for this analysis not yet defined
Secondary
Phase III Trial - Seizure Frequency
Seizure frequency by treatment group
Time frame: Day 1 - 540
Population: Final population numbers for this analysis not yet defined
Secondary
PK Substudy - Area Under the Curve of Praziquantel by Antiepileptic Drug in Treatment Day 1
\- To evaluate the kinetic disposition of Praziquantel by antiepileptic drug after the last praziquantel dose, we calculated the Area Under the Curve of Praziquantel with Carbamazepine or Phenytoin
Time frame: 0, 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 12 hours post dose in treatment day 1
Population: Carbamazepine and Phenytoin were not assigned by the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Albendazole + Praziquantel | PK Substudy - Area Under the Curve of Praziquantel by Antiepileptic Drug in Treatment Day 1 | Carbamazepine (n=8) | 548.3 ng*h / mL | Standard Deviation 320.9 |
| Albendazole + Praziquantel | PK Substudy - Area Under the Curve of Praziquantel by Antiepileptic Drug in Treatment Day 1 | Phenytoin (n=8) | 923.7 ng*h / mL | Standard Deviation 424.7 |
Secondary
PK Substudy - Area Under the Curve of Praziquantel by Antiepileptic Drug in Treatment Days 10 and 11
\- To evaluate the kinetic disposition of Praziquantel by antiepileptic drug after the last praziquantel dose, we calculated the Area Under the Curve of Praziquantel with Carbamazepine or Phenytoin
Time frame: 0.5, 1, 1.5, 2, 3, 4, 8, 10, 12, 24 and 36 hours post dose on treatment days 10-11
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Albendazole + Praziquantel | PK Substudy - Area Under the Curve of Praziquantel by Antiepileptic Drug in Treatment Days 10 and 11 | 240.2 ng*h/ml |
| Albendazole + Placebo | PK Substudy - Area Under the Curve of Praziquantel by Antiepileptic Drug in Treatment Days 10 and 11 | 550.1 ng*h/ml |
Secondary
PK Substudy - Safety of Combined Albendazole Plus Praziquantel Therapy
\- Describe if some Serious Adverse Event was associated to combined Albendazole plus Praziquantel therapy.
Time frame: 90 days post tx
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Albendazole + Praziquantel | PK Substudy - Safety of Combined Albendazole Plus Praziquantel Therapy | 0 Events |
| Albendazole + Placebo | PK Substudy - Safety of Combined Albendazole Plus Praziquantel Therapy | 0 Events |