# Presentation: 663694

## Picovir (Pleconaril)

- <date/time>

**Picovir ********(Pleconaril)**

**NDA 21-245**
**Treatment of acute VRI in adults**
**(Common Cold)**

## Agenda

**Overview of NDA and issues**
**Russ Fleischer, PA-C, MPH**
**Statistical review of efficacy**
**Thomas Hammerstrom, PhD**
**Safety and summary**
**Russ Fleischer, PA-C, MPH**

## Clinical Development Program

**VRI NDA 21-245 submitted July 31, 2001**
**2 pivotal studies**
**843-043 and 843-044  (400 mg TID x 5 days)**
**4 phase 2 studies**** **
**843-010 **
**843-013 **
**843-020**
**843-032**

## Application Issues

**Overall study results**
**Patient subgroups**
**Possible analysis populations**
**Identification of infected patients**
**Resistance **
**Food effect**
**Safety**

## Overall Study Results

**Difficulty demonstrating treatment effects **
**Enteroviral meningitis**
**Hand, foot, and mouth disease****	**
**Early VRI studies**
**Phase 3 VRI studies demonstrate **
**Median 0.5 day faster time to resolution in all randomized patients**
**Median 1.0 day faster time to resolution in infected patients**

## Patient Subgroups

**Discordant results in smokers **
**Difficulty drawing conclusions in elderly patients**
**Patients with co-morbid conditions  excluded from pivotal studies**

## Possible Analysis Populations

**Infected (ITT-I) **
**Identify infected patients**
**Demonstrate treatment effect**
**No harm in uninfected**
**All randomized (ITT)**
**More reflective of actual use**
**Prescribed based on symptoms with no rapid diagnostic assay**
**Prescribed to asymptomatic patients **

## Identification of Infected Patients

**Nasal mucus sample**

**TaqMan ******** RT-PCR Assay**

**ELOSA (RT-PCR) Assay**

**Virus Culture**

**PCR+**

**PCR-**

**PCR-**

**PCR+**

**61% PCR+**

**63% Culture+**

**PCR-**

## TaqMan RT-PCR Assay 

**Qualitative**
**Reported to detect 90/101 rhinovirus, 3/53 enterovirus, and 0/2 parechovirus serotypes**
**Sensitivity 93% (88-97%)**
**Assay run for 60 cycles **
**0.1 fluorescence level considered positive**
**Quantitative**
**Inadequate controls**
**Lack of reproducible sampling**
**Quantification of viral nucleic acid not validated**

## Fluorescence versus Cycle 

## ELOSA RT-PCR Assay

**Used to re-test TaqMan negative samples**
**Reported to identify 101/101 rhinovirus,  53/53 enterovirus, and 1/2 parechovirus serotypes **
**Sensitivity 97% for picornavirus**

## TaqMan and ELOSA Gel Analysis

## Viral Culture 

**Only PCR+ samples cultured**
**HeLa cells expressing ICAM at 33****o********C**
**Reported positive or negative based on presence of cytopathic effects**
**No serotyping conducted**

## Resistance in Pivotal Studies

**23.7% overall **
**13% baseline lack of susceptibility **
**10.7% loss of susceptibility (treatment-emergent)**
**No data on specific serotypes**
**3/4 with baseline lack of susceptibility had single amino acid change at VP1 position 98**
**Single amino acid substitutions led to     100-fold decrease in susceptibility**

## Time to Primary EndpointTreatment Emergent Resistance

- 						      **Median**
**	****	****	****	****	****	****         **_**days**_
**PBO****	****(n=333)****	****	****	****	****8.6**
**Pleconaril (n=286)****	****	****	****6.5**
**Pleconaril ****	****(n=28)****	****	****	****4.9**

## Time to Primary EndpointBaseline Lack of Susceptibility

## Food Effect

**Pleconaril exposure increased 4.0-6.5 fold with high fat/calorie meal**
**In hepatic impaired, AUC ********40% (18-55%)**
**Partially due to lower fat and meal **
**Patients instructed to take pleconaril within 15 minutes of full meal or snack**
**Adherence unknown**
**Impact on efficacy unknown**

## Safety

**General tolerability**
**Headaches**
**Nausea, vomiting, abdominal pain, diarrhea **
**CYP3A4 induction**
**Menstrual disorders**
**Potential for unintended pregnancies **
**Potential interactions with other medications**
**Tachycardia/palpitations**

## Pleconaril Adult Phase 2 7-day Treatment Studies

## Phase 2 Limitations

**Difficulty identifying infected patients**
**Outcomes impacted by**
**Uncontrolled and undocumented concomitant cold medication use**
**Inclusion of smokers**
**Inclusion of patients with fever**
**Inclusion of patients with allergic rhinitis**
**Stringent endpoints**
**Initiation of treatment late in disease**

## Studies 843-043 and 843-044Design

**Double-blind, placebo controlled **
**Healthy adults >18 years of age**
**Moderate to severe rhinorrhea**
**VRI symptoms **_**<**_**24 hours **
**Answer “yes” to “Are your symptoms due to a cold?”**
**Excluded allergic rhinitis, fever >100, underlying pulmonary, cardiac, immunocompromised, or serious illnesses**

## Studies 843-043 and 843-044Design

**Randomization stratified by**
**Smoking status**
**Pre-use of cold medications**
**400mg pleconaril or PBO TID x 5 days**
**Clinic visits day 3, 6, and 18**
**Patient diaries for 18.5 days **
**Acetaminophen/dextromethorphan provided**

## Studies 843-043 and 843-044Design

**Ordinal severity scores for rhinorrhea, nasal congestion, cough, pharyngeal signs, mylagia and malaise **
**Nasal mucus collected days 1, 3, and 6 for virologic testing**
**Experimental TaqMan PCR assay**
**Experimental ELOSA for TaqMan negative samples**
**Only PCR+ samples cultured**

## Studies 843-043 and 843-044 Demographics (ITT)

**	****	****	****	****	****	****    ****PBO****	****	****Pleconaril**
**	****	****	****	****	**** ****	****(n=1,050)****	**** ****(n=1,046)**
**Gender**
**  ****Male****	****	****	****	****    ****	****     ****31%****	****	****     ****31%**
**  ****Female****	****	****	****   ****	****     ****69%****	****	****     ****69%**
**Age (mean years)****	****	****   ****	****     ****36****	****	****     ****36**
**  ****Range****	****	****	****  ****	****   ****	****   ****18-86****	****	****   ****17-82**
**Smokers****	****	****	****	****     ****28%****	****	****     ****29%**
**Pre-treatment cold med users****	****   ****	****     ****30%****	****	****     ****30%**
**Median hours between first symptom****	****     ****19.8****	****	****     ****20.1**
**and first dose **
**Baseline severity score*****	****	****      ****	****       ****9****	****	****       ****9**
**PCR positive at baseline****	****	****	****     ****61%****	****	****     ****62%**

***Maximum score=18**

## Pleconaril Efficacy Results

**Thomas Hammerstrom, PhD**
**Statistical Reviewer**
**Division of Antiviral Drug Products**

## Phase 2 and 3 Clinical Trials

**Pivotal Phase 3 Trials 43 and 44**
**Endpoint: Time to no rhinorrhea, five other symptoms all mild or absent, and no cold medication use for 48 hours**
**Phase 2 Trials 10, 20 and 32**
**Endpoint: Time to no rhinorrhea, five other symptoms all mild or absent for 48 hours **
**Analysis populations: PCR+ and ITT**
**ELOSA assay for trials 20 and 32 **
**TaqMan plus ELOSA for trial 43 and 44**
**Results based on the two slightly different endpoints were nearly identical in studies 43 and 44**

## PCR and Culture Status(Trial 43)

**STATUS/ARM****	****	****	****	****  ****PBO****             ****Pleconaril**
**Enrolled****	****	****	****	****   ****526****	****	****   ****526**
**PCR positive at baseline****	****	****	**
**	****Positive culture****	****	****	****  **** 196****	****	****  **** 201**
**	****Negative culture****	****	****	****   ****104****	****	****   ****120**
**PCR negative at baseline, **
**	****positive day 3-6****	****    ****	****	****    ****24****	****	****    ****13**
**Total PCR positive****	****	****	****   ****324****	****	****   ****334**
**Never PCR positive****	****	****	****   ****202****	****	****   ****192**

## PCR and Culture Status(Trial 44)

**STATUS/ARM****	****	****	****	****  ****PBO****             ****Pleconaril**
**Enrolled****	****	****	****	****   ****524****	****	****   ****520**
**PCR positive at baseline****	****	****	**
**	****Positive culture****	****	****	****   ****224****	****	****   ****206**
**	****Negative culture****	****	****	****   ****115****	****	****   ****121**
**PCR negative at baseline, **
**	****positive day 3-6****	****    ****	****	****   **** 11****	****	****    ****16**
**Total PCR positive****	****	****	****  **** 350****	****	****   ****343**
**Never PCR positive****	****	****	****   ****174****	****	****   ****177**

## Quartiles of Time to HealingPCR+ Patients (ITT-I) 

_**Trial**_**	**_**Arm**_**	****	****  **_**N**_**	**_**Q1**_**	**_**Q2**_**	**** **_**Q3**_**	**_**p value**_
**43****	****	****PBO****	****	****300****	**** 5.0****	****7.5****	****12.5**
**	****	****Pleconaril****	****321****	**** 4.0****	****7.0****	****11.0****	****   0.023**
**44****	****	****PBO****	****	****339****	**** 5.0****	****8.5****	****12.5**
**	****	****Pleconaril****	****327****	**** 4.0****	****7.0****	****11.0****	****   0.008**

## Quartiles of Time to HealingAll Randomized Patients (ITT)

_**Trial**_**	**_**Arm**_**	****	****  **_**N**_**	**_**Q1**_**	**_**Q2**_**	**** **_**Q3**_**	**_**p value**_
**43****	****	****PBO****	****	****526****	**** 4.0****	****7.5****	****12.5**
**	****	****Pleconaril****	****526****	**** 4.0****	****7.0****	****11.5****	****   0.13**
**44****	****	****PBO****	****	****524****	**** 4.5****	****8.0****	****13.0**
**	****	****Pleconaril****	****520****	**** 4.0****	****7.0****	****11.5****	****   0.014**

## Quartiles of Time to HealingPCR+ Patients  

_**Trial**_**	**_**Arm**_**	****	****  **_**N**_**	**_**Q1**_**	**_**Q2**_**	**** **_**Q3**_**	**_**p value**_
**20****	****	****PBO****	****	****128****	**** 5.0****	****8.0****	****13.0**
**	****	****Pleconaril****	****147****	**** 5.0****	****9.0****	****13.0****	****   0.70**
**32****	****	****PBO****	****	****205****	**** 8.5****	****12.5****	****>20**
**	****	****Pleconaril****	****173****	**** 8.5****	****12.0****	****17.5****	****   0.51**

## Quartiles of Time to HealingAll Randomized 

_**Trial**_**	**_**Arm**_**	****	****  **_**N**_**	**_**Q1**_**	**_**Q2**_**	**** **_**Q3**_**	**_**p value**_
**20****	****	****PBO****	****	****334****	**** 5.0****	****8.0****	****15.0**
**	****	****Pleconaril****	****340****	**** 4.0****	****8.0****	****12.0****	****   0.011**
**32****	****	****PBO****	****	****432****	**** 8.0****	****12.0****	****19.5**
**	****	****Pleconaril****	****427****	**** 8.0****	****12.0****	****19.5****	****   0.82**

## Loss to Follow-UpPCR + Patients

_**Trial**_**	****	****	**_**43**_**	****	****	**_**44**_
**Arm****	****	****PBO****	****Pleconaril****	****PBO****	****Pleconaril****	**
**Enrolled****	****  ****300****	****      **** 321****	****	****  ****339****	****       ****327**
**Day 0****	****	****  **** 5****	****       ****11****	****	****   ****8****	****        ****6**
**Days 1-5****	****  ****11****	****         ****8****	****	****   ****5****	****        ****4**
**Days 6-15****	****   ****2****	****         ****2****	****	****   ****1****	****        ****3**
**Days **_**>**_**16****	****  ****46****	****      **** 46****	****	****  ****57****	****       ****46**

## Impact of Pre-Treatment Cold Medication Use (PCR+ Non-Users)

_**Trial**_**	**_**Arm**_**	****	****	****  **_**N**_**	**_**Q1**_**	**_**Q2**_**	**** **_**Q3**_**	**
**43****	****	****PBO****	****	****	****215****	****4.5****	****7.5****	****11.5**
**	****	****Pleconaril****	****	****220****	****3.5****	****6.5****	****10.5****	**** **
**44****	****	****PBO****	****	****	****219****	****5.0****	****8.5****	****12.5**
**	****	****Pleconaril****	****	****214****	****3.5****	****6.5****	****10.5****	**

## Impact of Pre-Treatment Cold Medication Use (PCR+ Users)

_**Trial**_**	**_**Arm**_**	****	****	****  **_**N**_**	**_**Q1**_**	**_**Q2**_**	**** **_**Q3**_**	**
**43****	****	****PBO****	****	****	****  85****	****6.5****	****9.0****	****14.5**
**	****	****Pleconaril****	****	****101****	****4.0****	****7.5****	****13.5****	**** **
**44****	****	****PBO****	****	****	****120****	****5.0****	****8.5****	****13.0**
**	****	****Pleconaril****	****	****113****	****4.5****	****8.5****	****12.0****	**

## Impact of Smoking(PCR+ Non-Smokers)

_**Trial**_**	**_**Arm**_**	****	****	****  **_**N**_**	**_**Q1**_**	**_**Q2**_**	**** **_**Q3**_**	**
**43****	****	****PBO****	****	****	****224****	****5.0****	****7.5****	****12.0**
**	****	****Pleconaril****	****	****219****	****3.5****	****6.5****	****10.5****	**** **
**44****	****	****PBO****	****	****	****249****	****5.0****	****8.5****	****12.5**
**	****	****Pleconaril****	****	****240****	****3.5****	****6.5****	****10.5****	**
**32****	****	****PBO****	****	****	****206****	****6.0****	****10.5****	****15.5**
**	****	****Pleconaril****	****	****173****	****5.5****	****  8.0****	****13.5****	**

## Impact of Smoking(PCR+ Smokers)

_**Trial**_**	**_**Arm**_**	****	****  ****	****  **_**N**_**	**_**Q1**_**	**_**Q2**_**	**** **_**Q3**_**	**
**43****	****	****PBO****	****	****  ****	****  76****	****5.5****	****8.0****	****13.5**
**	****	****Pleconaril****	****	****102****	****5.5****	****9.0****	****14.0****	**** **
**44****	****	****PBO****	****	**** ****	**** 90****	****5.0****	****8.5****	****12.5**
**	****	****Pleconaril****	****  ****	**** 87****	****5.5****	****9.0****	****15.0****	**
**32****	****	****PBO****	****	****  ****	**** 75****	****7.5****	****10.5****	****16.0**
**	****	****Pleconaril****	****  ****	**** 67****	****7.5****	****11.0****	****19.5****	**

## Gender Analysis-PCR+Trials 43 and 44

_**Gender**__**	**_** **_**Arm**_**	****	****  **_**N**_**	**_**Q1**_**	**_**Q2**_**	**** **_**Q3**_**	**
**Female****	****PBO****	****	****427****	****5.5****	****8.5****	****13.5**
**	****	****	****Pleconaril****	****439****	****4.0****	****7.0****	****11.5****	**** **
**Male****	****	****PBO****	****	****212****	****4.0****	****7.0****	****11.0**
**	****	****	****Pleconaril****	****209****	****3.0****	****6.0****	****11.0****	**

## Smokers by Gender-PCR+Trials 43 and 044

_**Gender**__**	**__**Arm**_**	****	****  **_**N**_**	**_**Q1**_**	**_**Q2**_**	**** **_**Q3**_**	**
**Female****	****PBO****	****	****109****	****5.5****	****9.0****	****13.0**
**	****	****	****Pleconaril****	****122****	****6.0****	****9.0****	****14.5****	**** **
**Male****	****	****PBO****	****	****  57****	****3.5****	****6.5****	****12.0**
**	****	****	****Pleconaril****	****  67****	****4.5****	****8.5****	****14.5****	**

## Time to Resolution of Individual Symptoms-Trial 43 (PCR+) 

_**Symptom**__**	**_**    **_**Arm**_**	****	****  **_**N**_**	**_**Q1**_**	**_**Q2**_**	**** **_**Q3**_**    **_**P**_**	**
**Rhinorrhea****	****PBO****	****	****300****	****4.0****	****7.0****	****11.0**
**	****	****	****Pleconaril****	****321****	****3.0****	****6.0****	****10.5   ****.040 **
**Congestion****	****PBO****	****	****284****	****4.0****	****6.5****	****10.0**
**	****	****	****Pleconaril****	****310****	****3.5****	****5.5****	****  8.5   ****.021**
**Cough****	****	****PBO****	****	****224****	****3.5****	****6.0****	****10.5**
**	****	****	****Pleconaril****	****251****	****3.0****	****6.0****	****11.0****    .51**
**Malaise****	****PBO****	****	****258****	****2.5****	****4.5****	****  8.0**
**	****	****	****Pleconaril****	****280****	****2.5****	****4.0****	****  6.5****   .039****	**

## Time to Resolution of Individual Symptoms-Trial 43 (PCR+) 

_**Symptom**__**	**_**    **_**Arm**_**	****	****  **_**N**_**	**_**Q1**_**	**_**Q2**_**	**** **_**Q3**_**    **_**P**_**	**
**Myalgia****	****PBO****	****	****160****	****2.5****	****3.5****	**** 6.0**
**	****	****	****Pleconaril****	****164****	****1.5****	****2.5****	**** 4.5   ****.0001**
**Sore throat****	****PBO****	****	****258****	****2.0****	****3.0****	**** 6.0**
**	****	****	****Pleconaril****	****274****	****1.5****	****2.5****	**** 4.5   ****.0001**
**Cold Med Use****	****PBO****	****	****109****	****2.0****	****3.0****	**** 5.0**
**	****	****	****Pleconaril****	****102****	****2.0****	****3.0****	**** 4.5   ****.24**
**	**

## Time to Resolution of Individual Symptoms-Trial 44 (PCR+) 

_**Symptom**__**	**_**    **_**Arm**_**	****	****  **_**N**_**	**_**Q1**_**	**_**Q2**_**	**** **_**Q3**_**    **_**P**_**	**
**Rhinorrhea****	****PBO****	****	****338****	****4.5****	****7.5****	****12.0**
**	****	****	****Pleconaril****	****327****	****3.0****	****6.0****	****10.5   ****.0023 **
**Congestion****	****PBO****	****	****317****	****4.0****	****6.5****	****10.0**
**	****	****	****Pleconaril****	****313****	****3.5****	****6.0****	****10.0   ****.20**
**Cough****	****	****PBO****	****	****232****	****3.5****	****7.0****	****12.5**
**	****	****	****Pleconaril****	****240****	****3.5****	****6.0****	****11.0****   .37**
**Malaise****	****PBO****	****	****292****	****3.0****	****4.0****	****  6.5**
**	****	****	****Pleconaril****	****274****	****2.5****	****4.0****	****  7.5****   .51****	**

## Time to Resolution of Individual Symptoms-Trial 44 (PCR+) 

_**Symptom**__**	**_**    **_**Arm**_**	****	****  **_**N**_**	**_**Q1**_**	**_**Q2**_**	**** **_**Q3**_**    **_**P**_**	**
**Myalgia****	****PBO****	****	****169****	****2.0****	****3.5****	**** 6.0**
**	****	****	****Pleconaril****	****157****	****2.0****	****3.0****	**** 6.0   ****.10**
**Sore throat****	****PBO****	****	****292****	****1.5****	****3.0****	**** 5.0**
**	****	****	****Pleconaril****	****274****	****1.5****	****3.0****	**** 5.0   ****.77**
**Cold Med Use****	****PBO****	****	****138****	****2.0****	****3.5****	**** 5.5**
**	****	****	****Pleconaril****	****109****	****2.0****	****3.0****	**** 5.0   ****.63**
**	**

## Secondary EndpointsPCR+ Patients

_**Trial**_**	**_**Endpoint**_**	**_**Pleconaril**_**	**_**PBO**_**	**_**Difference**_**      **_**P**_**	**
**43****	****	****Days impaired****	****    ****3.48****	****	****3.85****	****    ****-.38****	****         .19**
**44****	****	****Days impaired****	****    ****3.52****	****	****3.70****	****    ****-.17            .50**
**43****	****	****Nights impaired****   ****2.73****	****	****3.45****	****    ****-.72           .005**
**44****	****	****Nights impaired****   ****2.96****	****	****3.28****	****    -.31****	****        .20**
**43 ****	****Complications****	****     ****.08****	****	**** .06****	****     ****.02           .38**
**44****	****	****Complications****	****     ****.06****	****	**** .04****	****     ****.01****	****        .48****	**

## Efficacy Conclusions-1

**Pleconaril is statistically significantly superior to placebo in the PCR+ population**
**If the assay has low false negative rate, then the PCR+ population includes most infected subjects and statistical significance confirms the pleconaril effect**

## Efficacy Conclusions-2

**Pleconaril showed no statistically significant benefit in the PCR+ populations of trials 20 and 32, with a slightly different endpoint and slightly different recruitment criteria**
**Pleconaril will be used in the whole population, in which the estimated benefit is approximately 0.5 day**

## Efficacy Conclusions-3

**Pleconaril has no effect in smokers.  This absence of benefit has been confirmed in three separate studies: 43, 44, and 32**

## Safety Review

**VRI safety database (n=4,468)**
**2,488 treated with pleconaril**
**1,986 treated with placebo**
**No deaths or significant laboratory abnormalities**
**Adverse events generally similar**
**DCs due to adverse events similar**
**Headache, GI most common for both groups**

## General Adverse Events >2%in Pivotal Studies

**	****	****	****	****	****    ****  ****PBO****	****    ****	****Pleconaril**
**	****	****	****	****	**** **_**(n=1,050)**_**	**** **_**(n=1,046)**_
**Headache****	****	****	****      ****21%****	****	****     ****23%**
**Diarrhea****	****	****	****        ****7%****	****	****       ****7%**
**Nausea****	****	****	****	****        ****4%****	****	****       ****6%**
**Vomiting****	****	****	****        ****2%****	****	****       ****2%**
**Abdominal pain****	****	****	****        ****4%****	****	****       ****2%**
**Sinusitis****	****	****	****        ****2%****	****	****       ****3%**
**Bronchitis****	****	****	****        ****3%****	****	****       ****3%**
**Increased cough****	****	****	****        ****3%****	****	****       ****3%**
**Dizziness****	****	****	****        ****1%****	****	****       ****2%**
**Rhinitis****	****	****	****	****        ****3%****	****	****       ****2%**
**Menstrual disorders****	****	****      ****<1%****	****	****       ****2%**

## Menstrual Disorders 

**Early menses/intermenstrual bleeding, menorrhagia, menstrual disorder NOS**
**Observed in 5-7 day treatment studies**
**Significant increased frequency in 6-week prophylaxis study**
**Women re-consented**
**Barrier method recommended**
**Menstrual disorders targeted AEs**

## Menstrual Disorders

**Treatment Studies**

**Prophylaxis Study**

## CYP3A4 Induction

**IV midazolam AUC ********28% (24-33%)**
**Ethinyl estradiol AUC ********35% (29-40%)**
**No significant change in norethindrone PK**
**Single dose T****1/2 ****180 hours**
**Multiple dose T****1/2 ****>1000 hours**
**Maximum and duration of induction unknown**
**Potential to effect**
**immunosuppressants, antiarrhythmics, calcium channel blockers, protease inhibitors, Viagra******** **

## Potential Risk of Unintended Pregnancies

**20% OC users (n=690)**
**13 pregnancies **
**8 pleconaril **
**2 in 156 OC users (400 BID in 6-week study)**
**1 ongoing (EDC June 10, 2002)**
**1 abortion**
**5 placebo**
**1 in OC user**
**Outcome unknown**

## Potential Risk of Unintended Pregnancy

**CYP3A4 induction of ethinyl estradiol likely to impact at least entire cycle**
**10.4 million women between 15-44 used of a “pill” form of contraception***
**Expected OC failure ~1/100 women/year of use (range 0-2.5)**
**2/156 in 6 weeks appears higher than expected**
**Pleconaril not teratogenic, mutagenic, or genotoxic in animal studies**

***AGI, 1998**** **

## Tachycardia/Palpitations

**Theophylline CYP1A2 probe study**
**15 healthy theophylline-naïve volunteers**
**Theophylline 450 mg day 1, pleconaril 400 mg TID days 4-10, 450 mg theophylline dose on day 8**
**3/15 tachycardia/palpitations during pleconaril/theophylline administration**
****** ****abdominal pain, nausea, dizziness, syncope**
**Theophylline AUC ********15% (4%-28%)**
**No significant PK changes in 3 with palpitations**

## Tachycardia/Palpitations

**Adult VRI studies**
**7 pleconaril**** ****with palpitations/tachycardia (0.3%)**
**3 reported onset within one hour of ingestion**
**4 discontinued**
**1 serious (ER visit)**
**No pleconaril re-challenge**
**2 placebo (0.1%)**
**1 on day 5 within 1 hour**
**1 on day 2 within 30 minutes**

## Summary of Application Issues

**Overall study results**
**Efficacy in phase 2 not demonstrated**
**Efficacy in phase 3**
**0.5 day benefit in all randomized**
**1.0 day benefit in PCR+**
**Efficacy in smokers not demonstrated**
**No data in patients with co-morbid conditions**

## Summary of Application Issues

**Identification of infected patients possible **
**Quantitative performance not established**
**No serotyping of positive cultures**
**Resistance**
**Delayed resolution in patients with baseline lack of susceptibility**
**Shorter duration of illness in patients with loss of susceptibility **
**Single amino acid substitutions can lead to significant resistance**

## Summary of Application Issues

**Analysis populations**
**Expected uses**
**Prescribed to symptomatic with no diagnostic assay**
**Prescribed to asymptomatic for use at first symptom**
**Food requirement**
**Administration with a full meal **
**Requires initiation within 24 hours of symptom onset**

## Summary of Application Issues

**Safety**
**CYP3A4 induction**
**Menstrual disorders**
**Potential for OC failure and unintended pregnancies**
**Potential to impact efficacy of other medications **
**Tachycardia/palpitations**
**General tolerability**
**Headaches**
**Nausea, vomiting, abdominal pain, diarrhea**

## PleconarilReview Team

**Nara Battula**
**Anita Bigger**
**Jim Farrelly**
**Leslie Furlong**
**Zi Qiang Gu**
**Tom Hammerstrom**
**Katherine Laessig**
**Steve Miller**
**Julian O’Rear**

**Kellie Reynolds**
**Destry Sillivan**
**Greg Soon**
**Kathleen Whitaker**
**Jenny Zheng**