A Phase 1/2 Study to Evaluate the Safety, PK and Efficacy of TNP-2092 Administered Via IA Injection in Participants With Early or Acute Hematogenous PJI Requiring or Not Requiring DAIR After TKA, or Requiring Long-term Antibiotic Therapy
Phase: PHASE1
Conditions: Periprosthetic Joint Infection (PJI)
Sponsor: TenNor Therapeutics Inc.

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A Phase 1/2, randomized, controlled, open-label, Proof-of-Concept study to 
evaluate the safety and tolerability, pharmacokinetics, and efficacy of TNP-2092 
administered via intra-articular (IA) injection in adult participants with early or 
acute hematogenous prosthetic joint infection (PJI) requiring or not requiring 
debridement, antibiotics, and implants retention (DAIR) after total knee 
arthroplasty (TKA), or requiring long-term antibiotic suppression therapy 
 
 
 
 
Protocol  
 
 
 
 
Protocol No.: TNP-2092-IA-01 
 
 
 
 
Approval Date: 21 July 2025 
 
 
 
 
 
 
 

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PROTOCOL OF TNP-2092-IA-01 
Study title: 
A Phase 1/2, randomized, controlled, open-label, Proof-of-Concept study to evaluate the safety and 
tolerability, pharmacokinetics, and efficacy of TNP-2092 administered via intra-articular (IA) injection in 
adult participants with early or acute hematogenous prosthetic joint infection (PJI) requiring or not requiring 
debridement, antibiotics, and implants retention (DAIR) after total knee arthroplasty (TKA), or requiring 
long-term antibiotic suppression therapy. 
Study Population: 
Participants with early (within 1 month of TKA) or acute hematogenous (within 3 weeks of infection 
symptoms) PJI requiring or not requiring DAIR treatment after TKA, or requiring long-term antibiotic 
suppression therapy for PJI (including various joint replacement or revision surgeries). 
Investigational Site: 
The study is a clinical study conducted in China. 
Phase of Study: 1/2 
Study objectives: 
Primary objective 
 
To evaluate the safety and tolerability of TNP-2092 administrated via IA injection in adult participants 
with early (within 1 month of TKA) or acute hematogenous (within 3 weeks of infectious symptoms) PJI 
requiring or not requiring DAIR treatment after TKA, on the basis of vancomycin intravenous (IV) 
treatment combined with oral antibiotics. 
 
Secondary objectives 
 
To evaluate the systemic and local pharmacokinetic (PK) profile of TNP-2092 administered via IA 
injection for PJI. 
 
To evaluate the efficacy of TNP-2092 administered via IA injection for the treatment of early or acute 
hematogenous PJI, on the basis of background therapy. 
 
To evaluate the safety and tolerability of TNP-2092 administrated via IA injection for the treatment of 
PJI requiring long-term antibiotic suppression therapy, on the basis of background therapy. 
 
To evaluate the efficacy of TNP-2092 administrated via IA injection for the treatment of PJI requiring 
long-term antibiotic suppression therapy, on the basis of background therapy. 
Study Endpoints: 
1 
Safety and tolerability: 
Adverse events reported during the study, vital signs, physical examination, laboratory tests, etc. 
 
2 
Pharmacokinetic endpoints: 
Including concentrations of TNP-2092 in synovial fluid and PK parameters of TNP-2092 in plasma (if 
applicable). 
 
Synovial fluid 
◼ 
Drug concentrations at 12 h, 24 h after the first dose, before dosing on Day 7, and before the last 
dose, and at 12 h, 24 h, 48 h after the last dose. If the time points for PK sample collection are 
adjusted during the study, the drug concentrations at each adjusted time point will also be analyzed. 
 
Plasma 
◼ 
First dose of TNP-2092: time to maximum concentration (Tmax), maximum observed concentration 
(C max), elimination half-life (t1/2), area under the curve from the time of dosing to infinity (AUC0-
∞), area under the curve from the time of dosing to the last measurable concentration (AUC0-t), etc. 
◼ 
Last dose of TNP-2092: time to maximum concentration at steady state (Tmax, ss), maximum 
observed concentration at steady state (Cmax, ss), elimination half-life at steady state (t1/2, ss), area 
under the curve from time of dosing to the last measurable concentration at steady state (AUC0-t, ss), 
area under the curve from time of dosing to infinity at steady state (AUC 0- ∞, ss), area under the 
curve over the dosing interval at steady state (AUC0-tau, ss), accumulation ratio (Rac), etc. 

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3 
Efficacy Endpoints: 
a) 
Primary Efficacy Endpoint: 
i. 
Early Assessment (EA) response rate, after IV + IA treatment, participants with early or acute 
hematogenous PJI after TKA who meet all the following criteria will be judged as responders: 
⚫ 
At least 2 body temperature measurements within the last 24 hours separated by more 
than 6 hours were ≤ 37.6ºC. 
⚫ 
Peripheral white blood cell (WBC) count returned to normal range (as determined by 
local laboratory reference range). 
⚫ 
Synovial fluid WBC < 3000 cell/μL and polymorphonuclear leukocytes percentage 
(PMN%) < 80%. 
⚫ 
Inflammatory manifestations (pain, erythema, edema, wound exudate) at the primary 
infection site resolved, with pain requiring resolution or tolerance. 
⚫ 
Inflammatory markers (ie, C-reactive protein [CRP]) improved to 50% of normal or 
baseline values. 
b) 
Secondary Efficacy Endpoints: 
i. 
End of treatment (EOT) response rate, after 8 weeks of oral antibiotic therapy or background 
therapy, participants who meet all the following criteria will be judged as responders: 
⚫ 
Joint pain resolved or tolerated. 
⚫ 
Joint function improvement. 
⚫ 
Inflammatory markers (ie, CRP) returned to ≤ 10 mg/L. 
ii. 
Treatment failure rate within 6 months after the start of study treatment, and those who meet 
any of the following criteria will be judged as treatment failures: 
⚫ 
No response at EA assessment (only for participants with early or acute hematogenous 
PJI after TKA). 
⚫ 
No response at EOT assessment. 
⚫ 
Receiving systemic antibiotics for infected joints after the end of study treatment. 
⚫ 
Additional surgical treatment of infected joints is required during the study. 
⚫ 
Death due to primary joint infection. 
Study Design: 
This is a Phase 1/2, randomized, controlled, open-label, proof-of-concept study to evaluate the safety and 
tolerability, systemic and local pharmacokinetics, and efficacy of TNP-2092 administered via IA injection on 
the basis of background therapy in participants with early (within 1 month of TKA) or acute hematogenous 
(within 3 weeks of infectious symptoms) PJI requiring or not requiring DAIR therapy after TKA, or requiring 
long-term antibiotic suppression therapy for PJI (including various joint replacement or revision surgeries).  
 
The study population is participants with confirmed or suspected Gram-positive bacteria causing early (ie, 
within 1 month of TKA) or acute hematogenous (within 3 weeks of infection symptoms) PJI requiring or not 
requiring DAIR therapy after TKA, or requiring long-term antibiotic suppression therapy for PJI (including 
various joint replacement or revision surgeries). Participants will undergo screening assessments within 7 
days prior to start of the study. 
 

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First, three eligible participants will be enrolled as sentinel group to receive TNP-2092 50 mg IA once daily 
on the basis of vancomycin IV treatment (1 g every 12 h [q12 h], dose adjusted according to renal function), 
both IV and IA treatment will be last for 14 days, and participants will be assessed for EA after IA 
administration of TNP-2092 on D14. Participants will be transferred to oral antibiotics on D15 and continued 
to receive oral rifampicin capsules 0.45 g and levofloxacin tablets 0.5 g once daily, and participants who are 
intolerant to rifampicin and/or levofloxacin, or whose pathogens are resistant to rifampicin and/or 
levofloxacin could be switched to minocycline hydrochloride capsules orally every 12 hours, with the first 
dose doubled and 200 mg orally, followed by 100 mg each dose. Oral therapy will be administered for a total 
of 8 weeks (56 days). After oral treatment, participants will be evaluated by EOT from D71 to D77. 
Participants who meet the protocol-specified stopping criteria for oral antibiotics will enter the follow-up 
period. The investigator follows up the participants by telephone once a month and decides whether they 
needed to return to the study site for follow-up according to the situation until 6 months after the start of 
study treatment for efficacy evaluation (to confirm whether the participant 's disease status meet the protocol-
defined "treatment failure"), that is, the end-of-study (EOS) assessment. During the sentinel group study, the 
volume, dose, frequency and duration of TNP-2092 IA administration may be adjusted case-by-case after the 
investigator has fully discussed the decision with the sponsor. If IA treatment duration is adjusted, EA 
assessment will be performed after the end of IA treatment. Participants in the sentinel group will be 
discharged after all PK samples had been collected. 
 
During the study, if criteria for EA assessment or criteria for discontinuation of oral antibiotics are not met at 
the EOT assessment, the investigator will decide the subsequent treatment regimen and the participant will be 
withdrawn from the study. 
 
After all sentinel participants are tolerable safety at EA assessment and complete the PK study, an additional 
20 participants will be enrolled and randomize in 1:1 ratio to the experimental group (TNP-2092 IA + 
vancomycin IV + oral antibiotics) and the control group (vancomycin IA + vancomycin IV + oral antibiotics). 
The experimental group will be treated the same as the sentinel group (TNP-2092 dose volume, dose, 
frequency and duration can be adjusted according to the synovial fluid TNP-2092 concentration, PK profile, 
and safety results at the EA visit in the sentinel group); the control group will receive vancomycin IA + 
vancomycin IV + oral antibiotics. The study process of the two groups is the same as that of the sentinel 
group. Participants in the experimental group will be discharged after all PK samples are collected; 
participants in the control group will be discharged after completing EA assessments and IV + IA 
administration.  
 
Ten participants with PJI requiring long-term antibiotic suppression therapy (including various joint 
replacement or revision surgeries) will be enrolled in expansion group to receive TNP-2092 50 mg IA once 
daily on the basis of background therapy determined by the investigator. The volume, dose, and frequency of 
TNP-2092 administration may be adjusted according to the participant’s actual condition. TNP-2092 IA 
treatment will last for 14 days, followed by background treatment until the EOT assessment conducted 
between D71 and D77. Participants meeting the protocol-defined criteria for discontinuation of background 
therapy will enter the follow-up phase. The investigator will conduct monthly telephone follow-ups and 
determine whether a return to the research center for a visit is necessary, based on the participant’s condition. 
This will continue until 6 months after the initiation of study treatment, at which point an efficacy evaluation 
will be performed (confirming whether the participant's disease status meets the protocol-defined "treatment 
failure" criteria), marking the EOS assessment. Participants in the expansion group may be discharged after 
all PK samples are collected. The expansion group may enroll in parallel with the sentinel group, and the 
TNP-2092 IA administration volume, dose, frequency, duration, as well as the PK sample collection plan, 
may be adjusted synchronously with the sentinel group. If the IA treatment duration is adjusted, the 
expansion group’s EA assessment will be conducted after the completion of IA treatment. 
 

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During the screening period, samples of joint cavity puncture fluid and blood on the affected side will be 
obtained for Gram staining, culture and drug sensitivity test, and second-generation gene sequencing (NGS) 
detection will also be performed to determine the pathogen and drug resistance to the investigational product. 
After enrollment, if the participant has a negative culture result (i.e., no pathogenic microorganism is 
cultured), pathogenic bacteria will be determined by reference to NGS results, otherwise pathogenic bacteria 
will be determined based on culture results; if the participant requires DAIR treatment, samples such as 
blood, synovial fluid, infected joint tissue (if needed), knee spacer ultrasonic concussion fluid (if needed), 
and surgical area ultrasonic concussion fluid (if needed) will be collected during DAIR surgery for Gram 
staining, culture, and drug susceptibility testing, and pathogenic bacteria will be confirmed by reference to 
culture results. If no pathogenic bacteria can be identified (eg, culture, NGS results are negative), or PJI is 
confirmed to be caused by Gram-negative bacteria infection, fungal infection, or Enterococcus species 
infection, or mycobacterial infection, or Gram-positive bacteria mixed with Gram-negative bacteria and/or 
fungal infection, or blood culture shows systemic infection (sepsis), local intra-articular injection therapy will 
be discontinued, the investigator will treat the patient with appropriate antibiotics as appropriate, and the 
participant will withdraw from the study and will not be included in the efficacy assessment. 
Inclusion and exclusion criteria: 
Criteria for inclusion: 
Participants who meet all the following criteria were eligible for this study: 
1 
Early (within 1 month of TKA) or acute hematogenous (within 3 weeks of infectious symptoms) PJI 
requires or does not require DAIR therapy after TKA, or results of treatment for PJI (including PJI 
occurring after various joint replacements and revision surgeries) did not meet the clinical cure criteria 
and requiring long-term antibiotic suppression therapy as judged by investigators before enrollment. 
2 
Suspected or confirmed PJI caused by a Gram-positive bacterial infection, including methicillin-resistant 
and ciprofloxacin-resistant Staphylococcus aureus and Staphylococcus epidermidis, as judged by the 
investigator. 
3 
Agree to be hospitalized for 2 weeks with local intra-articular injection. 
4 
18 years of age or older (of either sex) at the time of signing the informed consent form (ICF). 
5 
The implanted prosthetic joint is well fixed. 
6 
No sinus tract that communicates with the prosthesis. 
7 
Body mass index (BMI) ≥ 18 kg/m 2 and ≤ 34 kg/m 2. 
8 
Agree to voluntarily use effective contraception from signing the ICF through 8 weeks after the last dose 
of investigational product (in case of premature withdrawal from the study) or through completion of the 
end-of-study visit. Male participants must refrain from donating sperm during this period. 
 
Exclusion Criteria: 
Participants who meet any of the following criteria were not included in the study: 
1 
History of hypersensitivity or intolerance to any of the following agents: vancomycin or TNP-2092. 
2 
Definite PJI of Gram-negative infection, fungal infection, or Enterococcus infection, or Mycobacterium 
infection, or Gram-positive mixed Gram-negative and/or fungal infection. 
3 
Definite systemic infection (sepsis). 
4 
Expected survival less than 1 year. 
5 
Female participant is pregnant, lactating, or has a positive screening/baseline pregnancy test. 
6 
Surgical or medical conditions that, in the opinion of the investigator, could affect the participant's ability 
to participate in the study, or affect the administration of investigational product, or affect the 
interpretation of study results, including but not limited to active malignancy, metabolic disease, alcohol 
or drug abuse, or clinically significant laboratory abnormalities. 
7 
Presence of serious liver, blood, or immune system disorders as evidenced by the following: 
a) 
Acute hepatitis of any cause within the past year. 
b) 
Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin 
levels > 2 times the upper limit of normal (ULN). 
c) 
Presence of end-stage liver disease-related manifestations such as ascites or hepatic 
encephalopathy. 
d) 
Current or anticipated neutropenia (ie, neutrophil count < 0.5 x 10 9/L). 

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e) 
Chemotherapy for cancer, radiation therapy, or potent noncorticosteroid immunosuppressants (eg, 
cyclosporine, azathioprine, tacrolimus, immunomodulatory monoclonal antibody therapy, etc) 
within the past 3 months or corticosteroids (≥ 40 mg prednisone/day) for more than 14 days within 
30 days prior to randomization. 
8 
Positive AIDS antibody screening. 
9 
History or evidence of severe renal disease or creatinine clearance < 30 mL/min based on the Cockcroft-
Gault formula. 
10 Treatment with an investigational agent within 30 days or 5 half-lives (whichever is longer) prior to the 
first dose of study intervention. 
11 Participants who, in the opinion of the investigator, were unable to comply with the protocol and study 
drug administration procedures or complete the clinical study. 
Study drug, dosage form, administration and dosage: 
The dosing schedule for the sentinel and randomized trial groups is as follows: 
 
Intravenous and intra-articular administration period: 
Intra-articular administration: TNP-2092 for injection, 100 mg/vial. A vial of lyophilized TNP-2092 (100 mg) 
will be dissolved with 6 mL of normal saline, and 3 mL of the drug solution (containing 50 mg TNP-2092) 
will be withdrawn and diluted with 7 mL of normal saline to finally prepare 10 mL of normal saline 
containing 50 mg TNP-2092. Administered by intra-articular injection, 10 mL (50 mg) once daily for 14 days 
at the same time of day (up to 1 hour earlier or later the basis of the first dose). If the participant 's joint had a 
drainage tube in place, the drainage tube will be closed for 12 hours after intra-articular administration, 
judged by the investigator based on the participant’s actual situation. If participant D1 requires DAIR surgery, 
the first dose should be administered intraoperatively. 
 
Intravenous infusion: Vancomycin Hydrochloride for Injection, 0.5 g/vial. Vancomycin 1 g will be dissolved 
in 20 mL normal saline and then diluted in 230 mL normal saline to finally prepare vancomycin 1 g in 250 
mL normal saline, and the intravenous drip time needs to be more than 60 min, q12h ± 1h per day, for 14 
days. If participant requires DAIR surgery on D1, the first dose should be administered after surgery. 
 
During the sentinel group study, the volume, dose, frequency and duration of TNP-2092 IA administration 
may be adjusted after the investigator has fully discussed the decision with the sponsor, depending on the 
participant 's actual situation. During the randomized study, the volume, dose, frequency and duration of 
TNP-2092 IA administration could be adjusted in the experimental group based on synovial fluid 
concentrations and PK profiles in the sentinel group and safety results at the EA visit. 
 
Oral Phase: 
Rifampicin capsules: 0.15 g/capsule. 0.45 g (3 capsules) orally once daily within 1 h before breakfast for 8 
weeks (56 days). 
 
Levofloxacin Tablets: 0.5 g/tablet. 0.5 g (1 tablet) orally once daily within 1 hour before breakfast for 8 
weeks (56 days). 
 
If susceptibility testing results show resistance to rifampicin and/or levofloxacin, or intolerance by the 
participant, treatment with oral minocycline hydrochloride capsules will be substituted as follows: 
 
Minocycline hydrochloride capsules: 100 mg/capsule. Administered orally q12h ± 1h daily, doubling the first 
dose, 200 mg (2 capsules) orally, then 100 mg (1 capsule) each time for 8 weeks (56 days). 
 
The total duration of oral treatment during the oral administration period is 8 weeks (56 days) regardless of 
whether oral medication will be changed (eg, intolerance). 
 
The dosing schedule for the expansion group is as follows: 
 

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Intra-articular administration: TNP-2092 for injection, 100 mg/vial. The preparation method is the same as 
above, and the final volume is determined by the investigator based on the actual condition of the participant, 
with the total volume ranging from 10 to 30 mL, containing TNP-2092 50 mg. Administered by intra-
articular injection once daily for 14 days at the same time of day (up to 1 hour earlier or later the basis of the 
first dose). If the participant 's joint had a drainage tube in place, the drainage tube will be closed for 12 hours 
after intra-articular administration, judged by the investigator based on the participant’s actual situation. 
During the study, the volume, dose, frequency and duration of TNP-2092 administrated IA could be adjusted 
based on the participant’s actual situation. 
 
Background treatment: Determined by the investigator. 
Control treatment, dosage form and dosage and administration: 
The dosing regimen for the control group after randomization was as follows: 
 
Intravenous and intra-articular administration period: 
Intra-articular: Vancomycin Hydrochloride for Injection, 0.5 g/vial. Vancomycin 0.5 g will be dissolved in 10 
mL of normal saline and administered as an intra-articular injection once a day, at the same time as possible 
(up to 1 hour earlier or later the basis of the first dose), 10 mL (0.5 g) per dose for 14 days. If the participant's 
joint had a drainage tube in place, the drainage tube will be closed for 12 hours after intra-articular 
administration, depending on the investigator' s actual situation of the participant. If participant requires 
DAIR surgery on D1, the first dose should be administered intraoperatively. 
 
Intravenous infusion: Vancomycin hydrochloride for injection: 1 g. Dosage and administration are the same 
as those in the sentinel group. 
 
Oral Phase: 
Drug selection, usage and dosage are the same as those in the sentinel group. 
Duration of participant participation: 
The entire study duration consists of a screening period of up to 1 week, an antibiotic treatment period of 
approximately 10 weeks (approximately 2 weeks IV + IA treatment and 8 weeks oral antibiotic treatment), 
and a follow-up period of approximately 3.5 months for approximately 6.25 months. 
Number of participants: 
Thirty-three evaluable participants are planned to be enrolled in this study, of which 23 are participants with 
early or acute hematogenous PJI after TKA, with the first 3 participants serving as sentinel groups, followed 
by 20 participants, 10 participants in the experimental group and 10 participants in the control group; ten 
participants are those requiring long-term antibiotic suppression therapy for PJI (including PJI occurring after 
virous joint replacement surgeries), will be enrolled in the expansion group, and in parallel with the sentinel 
group. Evaluable participants are those who completed Visit 5 (EA visit, participants with early or acute 
hematogenous PJI after TKA) or Visit 9 (EOT visit, participants requiring long-term antibiotic suppression 
therapy for PJI) and PK study (if applicable). 
Primary Statistical Analysis Methods: 
Analysis Population 
All analysis populations will be confirmed prior to study database lock. 
 
Full Analysis Set (FAS): includes all enrolled participants who received at least 1 dose of investigational 
product. Analyses will be performed by planned treatment group. 
 
Microbiological Intent-to-Treat Set (micro-ITT): includes all enrolled participants with etiologically 
confirmed Gram-positive bacterial infections (except Enterococcus spp., Mycobacterium spp.) who received 
at least 1 dose of investigational product. Analyses will be performed by planned treatment group. 
 
Safety set (SS): includes all participants who received at least one dose of investigational product after 
enrollment and have safety evaluation. Analyses will be performed by actual treatment group. 

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PK Concentration Analysis Set (PKCS): All enrolled participants who have used TNP-2092 and have at least 
one observed PK concentration comprised the PK concentration analysis set for this study. Analyses will be 
performed by actual dose group. 
 
PK Parameter Analysis Set (PKPS): All enrolled participants who have used TNP-2092 and have at least one 
PK parameter observed comprised the PK parameter analysis set for this study. Analyses will be performed 
by actual dose group. 
 
Safety and tolerability analysis 
Safety and tolerability of TNP-2092 IA treatment will be evaluated by treatment-emergent adverse events, 
serious adverse events, laboratory tests, vital signs, and physical examination results summarized by 
treatment group based on the SS analysis set. Descriptive statistics will be mainly performed for safety and 
tolerability. 
 
Pharmacokinetic analysis 
Based on the PKCS analysis set, TNP-2092 plasma and synovial fluid concentrations will be summarized by 
time point with descriptive statistics including the number of observations, arithmetic mean, standard 
deviation, arithmetic coefficient of variation (% CV), geometric mean, median, geometric% CV, minimum, 
and maximum. Plasma concentration-time data will be used to derive the following PK parameters using a 
noncompartmental model: first-dose PK parameters included Tmax, Cmax, t1/2, AUC0- ∞, AUC0-t, etc.; steady-
state PK parameters included Tmax, ss, Cmax, ss, t1/2, ss, AUC0-t, ss, AUC0- ∞,ss, AUC0-tau, ss, Rac, etc. Descriptive 
statistics for the PK parameters described above will be performed based on the PKPS analysis set and 
included the number of observations, arithmetic mean, standard deviation, %CV, geometric mean, median, 
geometric% CV, minimum, and maximum. Descriptive statistical analysis will not be performed for AUC0- ∞, 
t1/2, AUC_% Extrap if the residual area under the plasma concentration-time curve after dosing (AUC_% Extrap) is > 
20% in participants. 
 
Efficacy Analysis 
EA response rate, EOT response rate, 6-month treatment failure rate after start of IV + IA treatment, and other 
categorical variables will be described by frequency and percentage by dose group (if any) and treatment 
group based on the micro-ITT analysis set. Fisher 's exact test will be used to compare the experimental 
group with the control group in the randomization phase, and the 95% confidence interval (CI) for the rate 
difference between the experimental group and the control group will be estimated with the exact method. 
Continuous variables (e.g., laboratory test indicators) will be described by mean, standard deviation, median, 
maximum and minimum in different dose groups (if any) and treatment groups and compared between groups 
using t test or Wilcoxon rank sum test. Comparisons before and after treatment will be performed using 
paired t-test or signed rank sum test. Unless otherwise specified, all statistical tests will use a 2-sided test with 
alpha = 0.05 to calculate the 2-sided 95% CI. All statistical tests are exploratory. 
 
Sentinel group, randomized group and expansion group will be analyzed separately, and all participants will 
be combined for pooled analysis.