Title

Neurocysticercosis: Combined Treatment With Praziquantel (PZQ) and Albendazole (ABZ)
Antiparasitic Therapy for Neurocysticercosis: Phase II/III Study on Safety and Efficacy of Combined Treatment With Praziquantel and Albendazole
  • Phase

    Phase 2/Phase 3
  • Study Type

    Interventional
  • Study Participants

    156
The purpose of this study is to determine if combination drug therapy of praziquantel and albendazole is safe and effective to cure neurocysticercosis.
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.
Study Started
Jan 31
2010
Primary Completion
Dec 31
2012
Study Completion
Sep 30
2013
Results Posted
Aug 07
2013
Estimate
Last Update
Jun 11
2015
Estimate

Drug Praziquantel

- Praziquantel 50 mg / kg / d (up to 3600 mg / d ) for 10 days.

  • Other names: PZQ

Drug Albendazole

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.

  • Other names: ABZ

Drug ABZ Placebo

- Placebo (of Albendazole ) 7.5 mg / kg / d in Arm I and II for 10 days.

  • Other names: Placebo of Albendazole

Drug PZQ Placebo

- Placebo (of Praziquantel) 50 mg / kg / d in Arm II and III for 10 days.

  • Other names: Placebo of PZQ

I. ABZ + ABZ Placebo + PZQ Active Comparator

Albendazole 15 mg / kg / d (until 800 mg / d) + Placebo of Albendazole ( 7.5 mg / Kg / d )+ Praziquantel 50 mg / kg / d (until 3600 mg / d)

II.- ABZ + ABZ Placebo + PZQ Placebo Active Comparator

Albendazole 15 mg / kg / d ( until 800 mg / d ) + Placebo of Albendazole ( 7.5 mg / Kg / d ) + Placebo of Praziquantel ( 50 mg / kg / d )

III .- Albendazole + PZQ Placebo Active Comparator

Albendazole 22.5 mg / kg / d (until 1200 mg / d) + Placebo of Praziquantel ( 50 mg / kg / d ) This arm was not used in the first substudy ( initial part and guide to the design of the parent study ) however it will be used henceforward.

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.

Summary

Albendazole + Praziquantel

Albendazole + Placebo

All Events

Event Type Organ System Event Term Albendazole + Praziquantel Albendazole + Placebo

PK Substudy - Maximum Concentration of Albendazole

Highest serum level of Albendazole measured from all level assessments in the curve.

Albendazole + Praziquantel

1293.9
ng/mL (Mean)
Standard Deviation: 3471.6

Albendazole + Placebo

2232.8
ng/mL (Mean)
Standard Deviation: 6500.7

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).

Albendazole + Praziquantel

1412.2
ng*h/mL (Mean)
95% Confidence Interval: 58124.7

Albendazole + Placebo

1111.0
ng*h/mL (Mean)
95% Confidence Interval: 32257.1

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).

Albendazole + Praziquantel

4925.3
ng*h/ml (Mean)
95% Confidence Interval: 3548.6 to 6302.0

Albendazole + Placebo

2969.6
ng*h/ml (Mean)
95% Confidence Interval: 2543.8 to 3395.4

Phase III Trial - Proportion of Patients Without Remaining Live Cysts

Proportion of patients whose 6 month MR does not show viable parasites anymore

Phase III Trial - ABZ+PZQ

25.0
participants

Phase III Trial - Increased ABZ

19.0
participants

Phase III Trial - Standard ABZ

15.0
participants

PK Substudy - Safety of Combined Albendazole Plus Praziquantel Therapy

- Describe if some Serious Adverse Event was associated to combined Albendazole plus Praziquantel therapy.

Albendazole + Praziquantel

Albendazole + Placebo

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

Albendazole + Praziquantel

Carbamazepine (n=8)

548.3
ng*h / mL (Mean)
Standard Deviation: 320.9

Phenytoin (n=8)

923.7
ng*h / mL (Mean)
Standard Deviation: 424.7

Phase III Trial - Proportion of Cysts Which Resolved

Proportion of Viable Brain Parasites which Are not Alive Anymore at 6 Months MRI

Phase III Trial - ABZ+PZQ

Phase III Trial - Increased ABZ

Phase III Trial - Standard ABZ

Phase III Trial - Seizure Frequency

Seizure frequency by treatment group

Phase III Trial - ABZ+PZQ

Phase III Trial - Increased ABZ

Phase III Trial - Standard ABZ

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

Carbamazepine

240.2
ng*h/ml (Mean)
95% Confidence Interval: 151.7 to 328.7

Phenytoin

550.1
ng*h/ml (Mean)
95% Confidence Interval: 83.3 to 1183.4

Total

156
Participants

Age, Continuous

28
years (Mean)
Standard Deviation: 10.2

Age, Categorical

Region of Enrollment

Sex: Female, Male

Overall Study

PK Substudy ABZ+PZQ

PK Substudy ABZ+Placebo

Phase III Trial - ABZ+PZQ

Phase III Trial - Increased ABZ

Phase III Trial - Standard ABZ